2024-03-29T15:08:53Z
http://ir.lib.uwo.ca/do/oai/
oai:ir.lib.uwo.ca:mnipub-1000
2009-09-11T00:41:24Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:mni
publication:robarts
publication:institutes
18782028
Therapeutic Benefits of Regulating Inflammation in Autoimmunity
Nikoopour, Enayat
Schwartz, Jordan Ari
Singh, Bhagirath
Article
2008-09-01T07:00:00Z
Th17
inflammation
dendritic cells
autoimmunity
adjuvant
therapeutic use
immunoregulation.
Inflammation & Allergy - Drug Targets
Inflammation & Allergy - Drug Targets
7
3
203
210
Immunology and Infectious Disease
Microbiology
Autoimmunity results from the dysregulation of the immune system leading to tissue damage. Th1 and Th17 cells are known to be cellular mediators of inflammation in autoimmune diseases. The specific cytokine milieu within the site of inflammation or within secondary lymphatic tissues is important during the priming and effector phases of T cell response. In this review, we will address the nature of the inflammatory response in the context of autoimmune disease, specifically we will discuss the role of dendritic cells following stimulation of their innate pathogen recognition receptors in directing the development of T cell responses. We will focus on how dendritic cell subsets change the balance between
major players in autoimmunity, namely Th1, Th17 and regulatory T cells. Th17 cells, once thought to only act as pathogenic effectors through production of IL-17, have been shown to have regulatory properties as well with co-production of the anti-inflammatory cytokine IL-10 by a subset now referred to as regulatory Th17 cells. IL-17 is important in the induction of autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE) and inflammatory bowel disease (IBD). Study of the inflammatory process following encounter with agents that stimulate the innate immune responses such as adjuvants opens a new horizon for the discovery of therapeutic agents including those derived from microorganisms. Microbial products such as adjuvants that function as TLR ligands may stimulate the immune system by interacting with Toll-like receptors (TLR) on antigen presenting cells. Microbial agents such as Bacille Calmette-Guérin (BCG) or Freund's adjuvant (CFA) that induce a Th17 response are protective in models of autoimmune diseases particularly EAE and type 1 diabetes (T1D). The induction of innate immunity by these microbial products alters the balance in the cytokine microenvironment and may be responsible for modulation of the inflammation and protection from autoimmunity.
https://ir.lib.uwo.ca/mnipub/1
oai:ir.lib.uwo.ca:mnipub-1001
2009-09-11T00:36:05Z
publication:mnipub
publication:immunologypub
publication:faculties
publication:mni
publication:robarts
publication:institutes
Dendritic Cells and Immunoregulation in the Pathogenesis and Prevention of Type 1 Diabetes
Summers, Kelly L.
Marleau, Annette M.
Stephens, Tracey A.
Mahon, Jeffrey L.
Singh, Bhagirath
Article
2004-03-01T08:00:00Z
Autoimmune disease
Dendritic cells
Ep1.B
immunoregulation
T cells
tolerance
Canadian Journal of Diabetes
Canadian Journal of Diabetes
28
1
20
28
Immunology and Infectious Disease
Immunopathology
Microbiology
Dendritic cells govern the outcome of an immune response toward either tolerance or autoimmunity. Recent evidence has demonstrated that central tolerance is associated with relatively immature dendritic cells or quiescent mature dendritic cells that present self-antigens to autoreactive T cells, thereby silencing their autoreactive potential and/or activating regulatory T cells. Conversely, activated mature dendritic cells that have been instructed to become potent T cell stimulators by adjuvants or pathogens are capable of converting tolerance to immune activation. In combination with genetic and environmental influences, such mature dendritic cells are capable of orchestrating autoimmune responses. To explore the function of dendritic cells in type 1 diabetes, the authors evaluated peripheral dendritic cells from both patients with type 1 diabetes and the nonobese diabetic (NOD) mouse model that shares a pathologically analogous disease process.
Dendritic cells in NOD mice are phenotypically comparable to dendritic cells from autoimmune-resistant controls with respect to expression of differentiation molecules. However, in response to maturation stimuli, such cells confer heightened activation of T cells and excessive production of pro-inflammatory cytokines. These findings highlight a putative contribution of unabated dendritic cell activation to the loss of self-tolerance and to chronic, self- directed responses that define type 1 diabetes. Moreover, effective manipulation of dendritic cell activation state pro- vides a promising avenue for regulating autoimmunity. Using a novel self-derived peptide that programs dendritic cell maturation and activation from monocytic precursors, the authors demonstrated suppression of autoreactivity in the NOD mouse model of type 1 diabetes. Collectively, these data are consistent with a model in which dendritic cells at different maturation and activation states regulate peripheral tolerance vs. autoimmunity.
https://ir.lib.uwo.ca/mnipub/3
oai:ir.lib.uwo.ca:mnipub-1005
2009-10-10T01:15:35Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:mni
publication:robarts
publication:institutes
19647226
Tumor Suppression by Phospholipase C-beta3 via SHP-1-mediated Dephosphorylation of Stat5
Xiao, Wenbin
Hong, Hong
Kawakami, Yuko
Kato, Yuko
Wu, Dianqing
Yasudo, Hiroki
Kimura, Akiko
Kubagawa, Hiromi
Bertoli, Luigi F.
Davis, Randall S.
Chau, Luan A.
Madrenas, Joaquin
Hsia, Cyrus C.
Xenocostas, Anargyros
Kipps, Thomas J.
Hennighausen, Lothar
Iwama, Atsushi
Nakauchi, Hiromitsu
Kawakami, Toshiaki
Article
2009-08-04T07:00:00Z
Animals
Cell Differentiation
Cell Survival
Cell Transformation
Neoplastic
Hematopoietic Stem Cells
Lymphoma
Mice
Mutation
Myeloproliferative Disorders
Phospholipase C beta
Phosphorylation
Protein Tyrosine Phosphatase
Non-Receptor Type 6
Proto-Oncogene Proteins c-myc
STAT5 Transcription Factor
Signal Transduction
Tumor Suppressor Proteins
Cancer Cell
Cancer Cell
16
2
161
171
Immunology and Infectious Disease
Microbiology
Oncology
Given its catalytic activity to generate diacylglycerol and inositol 1,4,5-trisphosphate, phospholipase C (PLC) is implicated in promoting cell growth. However, we found that PLC-beta3-deficient mice develop myeloproliferative disease, lymphoma, and other tumors. The mutant mice have increased numbers of hematopoietic stem cells with increased proliferative, survival, and myeloid-differentiative abilities. These properties are dependent on Stat5 and can be antagonized by the protein phosphatase SHP-1. Stat5-dependent cooperative transformation by active c-Myc and PLC-beta3 deficiency was suggested in mouse lymphomas in PLC-beta3(-/-) and in Emicro-myc;PLC-beta3(+/-) mice and human Burkitt's lymphoma cells. The same mechanism for malignant transformation seems to be operative in other human lymphoid and myeloid malignancies. Thus, PLC-beta3 is likely a tumor suppressor.
Published in: Cancer Cell, Volume 16, Issue 2, 161-171, 4 August 2009. doi: 10.1016/j.ccr.2009.05.018
https://ir.lib.uwo.ca/mnipub/5
oai:ir.lib.uwo.ca:mnipub-1007
2009-10-10T02:12:08Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:mni
publication:robarts
publication:institutes
18981105
Dendritic Cell Differentiation Induced by a Self-Peptide Derived from Apolipoprotein E
Stephens, Tracey A.
Nikoopour, Enayat
Rider, Beverly J.
Leon-Ponte, Matilde
Chau, Thu A.
Mikolajczak, Sebastian
Chaturvedi, Pratibha
Lee-Chan, Edwin
Flavell, Richard A.
Haeryfar, S M Mansour
Madrenas, Joaquin
Singh, Bhagirath
Article
2008-11-15T08:00:00Z
Animals
Apolipoproteins E
Blotting
Western
Cell Adhesion
Cell Differentiation
Cell Line
Dendritic Cells
Flow Cytometry
Humans
Lymphocyte Activation
Lymphocyte Culture Test
Mixed
Mice
Peptide Fragments
Signal Transduction
T-Lymphocytes
The Journal of Immunology
The Journal of Immunology
181
10
6859
6871
Immunology and Infectious Disease
Microbiology
Dendritic cells (DCs) are professional APCs and potent stimulators of naive T cells. Since DCs have the ability to immunize or tolerize T cells they are unique candidates for use in immunotherapy. Our laboratory has discovered that a naturally processed self-peptide from apolipoprotein E, Ep1.B, induces DC-like morphology and surface marker expression in a murine monocytic cell line (PU5-1.8), human monocytic cell line (U937), murine splenocytes, and human peripheral blood monocytes. Microscopy and flow cytometric analysis revealed that Ep1.B-treated cells display decreased adherence to plastic and increased aggregation, dendritic processes, and expression of DC surface markers, including DEC-205, CD11c, B7.1, and B7.2. These effects were observed in both PU5-1.8 cells and splenocytes from various mouse strains including BALB/c, C57BL/6, NOD/Lt, and C3H/HeJ. Coadministration of Ep1.B with OVA antigenic peptide functions in dampening specific immune response to OVA. Ep1.B down-regulates proliferation of T cells and IFN-gamma production and stimulates IL-10 secretion in immunized mice. Ep1.B-induced differentiation resulted in the activation of PI3K and MAPK signaling pathways, including ERK1/2, p38, and JNK. We also found that NF-kappaB, a transcription factor essential for DC differentiation, is critical in mediating the effects of Ep1.B. Ep1.B-induced differentiation is independent of MyD88-dependent pathway of TLR signaling. Cumulatively, these findings suggest that Ep1.B acts by initiating a signal transduction cascade in monocytes leading to their differentiation into DCs.
https://ir.lib.uwo.ca/mnipub/7
oai:ir.lib.uwo.ca:mnipub-1008
2009-10-10T02:21:30Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:mni
publication:robarts
publication:institutes
18714010
Molecular Requirements for MHC Class II {alpha}-Chain Engagement and Allelic Discrimination by the Bacterial Superantigen Streptococcal Pyrogenic Exotoxin C
Kasper, Katherine J.
Xi, Wang
Nur-Ur Rahman, A. K. M.
Nooh, Mohammed M.
Kotb, Malak
Sundberg, Eric J.
Madrenas, Joaquín
McCormick, John K.
Article
2008-09-01T07:00:00Z
Bacterial Proteins
Cell Line
Epitope Mapping
Epitopes
Exotoxins
Histocompatibility Antigens Class II
Humans
Jurkat Cells
Lymphocyte Activation
Protein Interaction Domains and Motifs
T-Lymphocytes
The Journal of Immunology
The Journal of Immunology
181
5
3384
3392
Immunology and Infectious Disease
Microbiology
Superantigens (SAgs) are microbial toxins that bind to both TCR beta-chain variable domains (Vbetas) and MHC class II molecules, resulting in the activation of T cells in a Vbeta-specific manner. It is now well established that different isoforms of MHC II molecules can play a significant role in the immune response to bacterial SAgs. In this work, using directed mutational studies in conjunction with functional analyses, we provide a complete functional map of the low-affinity MHC II alpha-chain binding interface of the SAg streptococcal pyrogenic exotoxin C (SpeC) and identify a functional epitope in the beta-barrel domain that is required for the activation of T cells. Using cell lines that exclusively express individual MHC II isoforms, our studies provide a molecular basis for the selectivity of SpeC-MHC II recognition, and provide one mechanism by how SAgs are capable of distinguishing between different MHC II alleles.
https://ir.lib.uwo.ca/mnipub/8
oai:ir.lib.uwo.ca:immunologypub-1004
2009-10-10T02:37:46Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
18634825
Characterization of Oligomers Induced by Inverse Agonists of CTLA-4
Teft, Wendy A.
Madrenas, Joaquín
Article
2008-10-30T07:00:00Z
Actins
Antibodies
Bispecific
Antigens
CD
Antigens
CD86
Antigens
Surface
Gene Expression Regulation
Humans
Immunoglobulin Variable Region
Jurkat Cells
Membrane Microdomains
T-Lymphocytes
Immunology Letters
Immunology Letters
120
1-2
29
36
Immunology and Infectious Disease
Although cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) inhibits T cell activation when ligated by B7 molecules on antigen-presenting cells, it can also act as an activating receptor when binding certain soluble recombinant ligands known as inverse agonists. Following ligation with an inverse agonist, we observed CTLA-4 microclusters evenly distributed on the T cell surface over a 60-min period. We have previously shown that the inverse agonist properties of these ligands correlate with their capacity to induce the formation of large CTLA-4 oligomers that are distinctly different from those resulting by CTLA-4 engagement with membrane-bound B7. These oligomers are composed of CTLA-4 molecules expressed on the cell surface and decrease from both the soluble cell lysate and lipid rafts upon cellular fractionation. Formation of these inverse agonist-induced CTLA-4 oligomers does not require an intact actin cytoskeleton. However, modulation of these oligomers was partially blocked upon actin depolymerization. Retention of CTLA-4 oligomers on the cell surface correlated with enhanced T cell signaling. Together, our data further characterize the structural basis of inverse agonist properties for CTLA-4 ligands that may be used in the design and screening of therapeutic biologicals targeting this receptor.
Published in: Immunology Letters, Volume 120, Issues 1-2, 30 September 2008, Pages 29-36. doi: 10.1016/j.imlet.2008.06.005
https://ir.lib.uwo.ca/immunologypub/4
oai:ir.lib.uwo.ca:immunologypub-1002
2009-10-10T01:56:54Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
19405949
Structure-function Analysis of the CTLA-4 Interaction with PP2A
Teft, Wendy A.
Chau, Thu A.
Madrenas, Joaquín
Article
2009-04-30T07:00:00Z
Antigens
CD
Enzyme Activation
Humans
Jurkat Cells
Lymphocyte Activation
Mutagenesis
Site-Directed
Mutation
Okadaic Acid
Protein Binding
Protein Interaction Domains and Motifs
Protein Phosphatase 2
Protein Structure
Tertiary
Structure-Activity Relationship
T-Lymphocytes
Transgenes
BMC Immunology
BMC Immunology
10
23
Immunology and Infectious Disease
Background: CTLA-4 functions primarily as an inhibitor of T cell activation. There are several candidate explanations as to how CTLA-4 modulates T cell responses, but the exact mechanism remains undefined. The tail of CTLA-4 does not have any intrinsic enzymatic activity but is able to associate with several signaling molecules including the serine/threonine phosphatase PP2A. PP2A is a heterotrimeric molecule comprised of a regulatory B subunit associated with a core dimer of a scaffolding (A) and a catalytic (C) subunit.
Results: Here, we performed an analysis of the human CTLA-4 interface interacting with PP2A. We show that PP2A interacts with the cytoplasmic tail of CTLA-4 in two different sites, one on the lysine rich motif, and the other on the tyrosine residue located at position 182 (but not the tyrosine 165 of the YVKM motif). Although the interaction between CTLA-4 and PP2A was not required for inhibition of T cell responses, it was important for T cell activation by inverse agonists of CTLA-4. Such an interaction was functionally relevant because the inverse agonists induced IL-2 production in an okadaic acid-dependent manner.
Conclusion: Our studies demonstrate that PP2A interacts with the cytoplasmic tail of human CTLA-4 through two motifs, the lysine rich motif centered at lysine 155 and the tyrosine residue 182. This interaction and the phosphatase activity of PP2A are important for CTLA-4-mediated T cell activation.
Published in: BMC Immunology, 2009, 10:23. doi:10.1186/1471-2172-10-23
https://ir.lib.uwo.ca/immunologypub/2
oai:ir.lib.uwo.ca:immunologypub-1003
2009-10-10T02:31:39Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:mni
publication:robarts
publication:institutes
18641330
Modulation of T Cell Activation by Stomatin-Like Protein 2
Kirchhof, Mark G.
Chau, Luan A.
Lemke, Caitlin D.
Vardhana, Santosh
Darlington, Peter J.
Márquez, Maria E.
Taylor, Roy
Rizkalla, Kamilia
Blanca, Isaac
Dustin, Michael L.
Madrenas, Joaquín
Article
2008-08-01T07:00:00Z
Actins
B-Lymphocytes
Blood Proteins
Cells
Cultured
Humans
Interleukin-2
Lymphocyte Activation
Lymphoid Tissue
Membrane Proteins
Protein Binding
Protein Transport
RNA
Small Interfering
Receptors
Antigen
T-Cell
T-Lymphocytes
Up-Regulation
The Journal of Immunology
The Journal of Immunology
181
3
1927
1936
Immunology and Infectious Disease
T cell activation through the Ag receptor (TCR) requires sustained signaling from signalosomes within lipid raft microdomains in the plasma membrane. In a proteomic analysis of lipid rafts from human T cells, we identified stomatin-like protein (SLP)-2 as a candidate molecule involved in T cell activation through the Ag receptor. In this study, we show that SLP-2 expression in human primary lymphocytes is up-regulated following in vivo and ex vivo activation. In activated T cells, SLP-2 interacts with components of TCR signalosomes and with polymerized actin. More importantly, up-regulation of SLP-2 expression in human T cell lines and primary peripheral blood T cells increases effector responses, whereas down-regulation of SLP-2 expression correlates with loss of sustained TCR signaling and decreased T cell activation. Our data suggest that SLP-2 is an important player in T cell activation by ensuring sustained TCR signaling, which is required for full effector T cell differentiation, and point to SLP-2 as a potential target for immunomodulation.
https://ir.lib.uwo.ca/immunologypub/3
oai:ir.lib.uwo.ca:mnipub-1006
2009-10-10T01:29:52Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
19659771
Attenuation of Massive Cytokine Response to the Staphylococcal Enterotoxin B Superantigen by the Innate Immunomodulatory Protein Lactoferrin
Hayworth, J. L.
Kasper, K. J.
Leon-Ponte, M.
Herfst, C. A.
Yue, D.
Brintnell, W. C.
Mazzuca, D. M.
Heinrichs, D. E.
Cairns, E.
Madrenas, J.
Hoskin, D. W.
McCormick, J. K.
Haeryfar, S. M. M.
Article
2009-07-01T07:00:00Z
Animals
Anti-Bacterial Agents
Apoproteins
Cattle
Cell Proliferation
Enterotoxins
Female
Flow Cytometry
HLA-DR4 Antigen
Humans
Interleukin-2
Jurkat Cells
Lactoferrin
Lymphocyte Activation
Male
Mice
Mice
Inbred C57BL
Mice
Transgenic
Serum Albumin
Staphylococcal Infections
Superantigens
T-Lymphocytes
Transferrin
Clinical & Experimental Immunology
Clinical & Experimental Immunology
157
1
60
70
Immunology and Infectious Disease
Microbiology
Staphylococcal enterotoxin B (SEB) is a pyrogenic exotoxin and a potent superantigen which causes massive T cell activation and cytokine secretion, leading to profound immunosuppression and morbidity. The inhibition of SEB-induced responses is thus considered a goal in the management of certain types of staphylococcal infections. Lactoferrin (LF) is a multi-functional glycoprotein with both bacteriostatic and bactericidal activities. In addition, LF is known to have potent immunomodulatory properties. Given the anti-microbial and anti-inflammatory properties of this protein, we hypothesized that LF can modulate T cell responses to SEB. Here, we report that bovine LF (bLF) was indeed able to attenuate SEB-induced proliferation, interleukin-2 production and CD25 expression by human leucocyte antigen (HLA)-DR4 transgenic mouse T cells. This inhibition was not due to bLF's iron-binding capacity, and could be mimicked by the bLF-derived peptide lactoferricin. Cytokine secretion by an engineered SEB-responsive human Jurkat T cell line and by peripheral blood mononuclear cells from healthy donors was also inhibited by bLF. These findings reveal a previously unrecognized property of LF in modulation of SEB-triggered immune activation and suggest a therapeutic potential for this naturally occurring protein during toxic shock syndrome.
Published in: Clinical & Experimental Immunology,
Volume 157, Issue 1, Pages 60 - 70. doi: 10.1111/j.1365-2249.2009.03963.x
https://ir.lib.uwo.ca/mnipub/6
oai:ir.lib.uwo.ca:immunologypub-1001
2009-10-10T01:57:37Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
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publication:med
publication:mni
publication:robarts
publication:institutes
19465927
Toll-like Receptor 2 Ligands on the Staphylococcal Cell Wall Downregulate Superantigen-induced T Cell Activation and Prevent Toxic Shock Syndrome
Chau, Thu A.
McCully, Michelle L.
Brintnell, William
An, Gary
Kasper, Katherine J.
Vinés, Enrique D.
Kubes, Paul
Haeryfar, S. M. Mansour
McCormick, John K.
Cairns, Ewa
Heinrichs, David E.
Madrenas, Joaquín
Article
2009-06-01T07:00:00Z
Animals
Antigen-Presenting Cells
Antigens
Bacterial
Apoptosis
Cell Wall
Down-Regulation
Humans
Interleukin-2
Ligands
Lymphocyte Activation
Mice
NF-kappa B
Shock
Septic
Staphylococcus aureus
Superantigens
T-Lymphocytes
Toll-Like Receptor 2
Nature Medicine
Nature Medicine
15
6
641
648
Immunology and Infectious Disease
Staphylococcal superantigens are pyrogenic exotoxins that cause massive T cell activation leading to toxic shock syndrome and death. Despite the strong adaptive immune response induced by these toxins, infections by superantigen-producing staphylococci are very common clinical events. We hypothesized that this may be partly a result of staphylococcal strains having developed strategies that downregulate the T cell response to these toxins. Here we show that the human interleukin-2 response to staphylococcal superantigens is inhibited by the simultaneous presence of bacteria. Such a downregulatory effect is the result of peptidoglycan-embedded molecules binding to Toll-like receptor 2 and inducing interleukin-10 production and apoptosis of antigen-presenting cells. We corroborated these findings in vivo by showing substantial prevention of mortality after simultaneous administration of staphylococcal enterotoxin B with either heat-killed staphylococci or Staphylococcus aureus peptidoglycan in mouse models of superantigen-induced toxic shock syndrome.
Published in: Nature Medicine 15, 641 - 648 (2009). doi:10.1038/nm.1965
https://ir.lib.uwo.ca/immunologypub/1
oai:ir.lib.uwo.ca:immunologypub-1005
2009-10-12T01:26:57Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
18598105
The Future of RIP2/RICK/CARDIAK as a Biomarker of the Inflammatory Response to Infection
McCully, Michelle L.
Fairhead, Todd
Blake, Peter G.
Madrenas, Joaquin
Article
2008-05-01T07:00:00Z
Biological Markers
Humans
Infection
Inflammation
Peritoneal Dialysis
Peritonitis
Receptor-Interacting Protein Serine-Threonine Kinase 2
Expert Review of Molecular Diagnostics
Expert Review of Molecular Diagnostics
8
3
257
261
Immunology and Infectious Disease
Biological markers of disease have become increasingly important for the clinician to diagnose, predict and monitor progression, and assess the therapeutic effect of interventions on underlying pathogenic mechanisms. Robust and specific biomarkers would be very useful in inflammation, where they may facilitate early identification of tissue injury, predict disease progression and help to modify disease outcomes. However, at present, there are no robust biomarkers to predict the course of inflammation. Here, we discuss emerging data indicating that RIP2, a putative serine/threonine protein kinase, may serve as a biomarker for the resolution of peritoneal dialysis-associated peritonitis and, more generally, of the acute inflammatory response to infection.
Published in: Expert Review of Molecular Diagnostics,
May 2008, Vol. 8, No. 3, Pages 257-261. DOI: 10.1586/14737159.8.3.257
https://ir.lib.uwo.ca/immunologypub/5
oai:ir.lib.uwo.ca:mnipub-1009
2009-10-11T20:49:19Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
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publication:robarts
publication:institutes
19210755
Mesenchymal Stem Cells and Their Use as Cell Replacement Therapy and Disease Modelling Tool
García-Castro, J.
Trigueros, C.
Madrenas, Joaquin
Pérez-Simón, J. A.
Rodriguez, R.
Menendez, P.
Article
2008-12-01T08:00:00Z
Animals
Clinical Trials as Topic
Disease
Humans
Immune Tolerance
Mesenchymal Stem Cell Transplantation
Mesenchymal Stem Cells
Models
Biological
Journal of Cellular and Molecular Medicine
Journal of Cellular and Molecular Medicine
12
6B
2552
2565
Immunology and Infectious Disease
Microbiology
Mesenchymal stem cells (MSCs) from adult somatic tissues may differentiate in vitro and in vivo into multiple mesodermal tissues including bone, cartilage, adipose tissue, tendon, ligament or even muscle. MSCs preferentially home to damaged tissues where they exert their therapeutic potential. A striking feature of the MSCs is their low inherent immunogenicity as they induce little, if any, proliferation of allogeneic lymphocytes and antigen-presenting cells. Instead, MSCs appear to be immunosuppressive in vitro. Their multilineage differentiation potential coupled to their immuno-privileged properties is being exploited worldwide for both autologous and allogeneic cell replacement strategies. Here, we introduce the readers to the biology of MSCs and the mechanisms underlying immune tolerance. We then outline potential cell replacement strategies and clinical applications based on the MSCs immunological properties. Ongoing clinical trials for graft-versus-host-disease, haematopoietic recovery after co-transplantation of MSCs along with haematopoietic stem cells and tissue repair are discussed. Finally, we review the emerging area based on the use of MSCs as a target cell subset for either spontaneous or induced neoplastic transformation and, for modelling non-haematological mesenchymal cancers such as sarcomas.
Published in: Journal of Cellular and Molecular Medicine,
Volume 12 Issue 6b, Pages 2552 - 2565. doi: 10.1111/j.1582-4934.2008.00516.x
https://ir.lib.uwo.ca/mnipub/9
oai:ir.lib.uwo.ca:mnipub-1010
2009-10-12T01:43:43Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:mni
publication:robarts
publication:institutes
17303163
Crystal Structure of the Streptococcal Superantigen SpeI and Functional Role of a Novel Loop Domain in T Cell Activation by Group V Superantigens
Brouillard, Jean-Nicholas P.
Günther, Sebastian
Varma, Ashok K.
Gryski, Irene
Herfst, Christine A.
Rahman, A. K. M. Nur-ur
Leung, Donald Y. M.
Schlievert, Patrick M.
Madrenas, Joaquin
Sundberg, Eric J.
McCormick, John K.
Article
2007-04-06T07:00:00Z
Amino Acid Sequence
Antigens
Bacterial
Bacterial Proteins
Crystallography
X-Ray
Epitopes
T-Lymphocyte
Evolution
Molecular
Exotoxins
Humans
Lymphocyte Activation
Models
Molecular
Molecular Sequence Data
Phylogeny
Protein Structure
Tertiary
Pyrogens
Sequence Homology
Amino Acid
Superantigens
Journal of Molecular Biology
Journal of Molecular Biology
367
4
925
934
Immunology and Infectious Disease
Microbiology
Superantigens (SAgs) are potent microbial toxins that bind simultaneously to T cell receptors (TCRs) and class II major histocompatibility complex molecules, resulting in the activation and expansion of large T cell subsets and the onset of numerous human diseases. Within the bacterial SAg family, streptococcal pyrogenic exotoxin I (SpeI) has been classified as belonging to the group V SAg subclass, which are characterized by a unique, relatively conserved approximately 15 amino acid extension (amino acid residues 154 to 170 in SpeI; herein referred to as the alpha3-beta8 loop), absent in SAg groups I through IV. Here, we report the crystal structure of SpeI at 1.56 A resolution. Although the alpha3-beta8 loop in SpeI is several residues shorter than that of another group V SAg, staphylococcal enterotoxin serotype I, the C-terminal portions of these loops, which are located adjacent to the putative TCR binding site, are structurally similar. Mutagenesis and subsequent functional analysis of SpeI indicates that TCR beta-chains are likely engaged in a similar general orientation as other characterized SAgs. We show, however, that the alpha3-beta8 loop length, and the presence of key glycine residues, are necessary for optimal activation of T cells. Based on Vbeta-skewing analysis of human T cells activated with SpeI and structural models, we propose that the alpha3-beta8 loop is positioned to form productive intermolecular contacts with the TCR beta-chain, likely in framework region 3, and that these contacts are required for optimal TCR recognition by SpeI, and likely all other group V SAgs.
Published in: Journal of Molecular Biology, Volume 367, Issue 4, 6 April 2007, Pages 925-934. doi: 10.1016/j.jmb.2007.01.024
https://ir.lib.uwo.ca/mnipub/10
oai:ir.lib.uwo.ca:immunologypub-1007
2009-10-12T01:29:01Z
publication:mnipub
publication:patholpub
publication:surgerypub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:pathol
publication:med
publication:mni
publication:robarts
publication:surgery
publication:institutes
18522545
RIP2 Is Required for NOD Signaling But Not for Th1 Cell Differentiation and Cellular Allograft Rejection
Fairhead, T.
Lian, D.
McCully, Michelle L.
Garcia, B.
Zhong, R.
Madrenas, J.
Article
2008-06-01T07:00:00Z
Animals
Cell Differentiation
Disease Models
Animal
Graft Rejection
Mice
NF-kappa B
Oxygenases
Receptor-Interacting Protein Serine-Threonine Kinases
Signal Transduction
Th1 Cells
American Journal of Transplantation
American Journal of Transplantation
8
6
1143
1150
Immunology and Infectious Disease
Two previous reports that receptor-interacting protein (RIP)-2 knockout (RIP2-/-) mice had defective nuclear factor-kappa B (NF-kappaB) signaling and T helper (Th)1 immune responses had led us to believe that this putative serine-threonine kinase might be a possible target for transplant immunosuppression. Thus, we tested whether RIP2-/- mice were able to reject vascularized allografts. Surprisingly, we found that T cells from RIP2-/- mice proliferated and produced interferon (IFN)-gamma after allostimulation in vitro. Moreover, naïve RIP2-/- CD4+ T cells differentiated normally into Th1 or Th2 cells under appropriate cytokine microenvironments. Consistent with these findings, no difference in allograft survival was observed between wild-type and RIP2-/- recipient mice, and rejection had similar pathology and cytokine profiles in both types of recipients. RIP2 deficiency was associated with defective NOD signaling, but this did not affect T-cell receptor (TCR)-dependent activation of the canonical NF-kappaB signaling or expression of NF-kappaB genes in rejecting allografts. Our data demonstrate that RIP2-deficient mice have intact canonical NF-kappaB signaling and can mount Th1-mediated alloresponses and reject vascularized allografts as efficiently as wild-type mice, thus arguing against RIP2 as a primary target for immunosuppression.
Published in: American Journal of Transplantation,
Volume 8, Issue 6, Pages 1143 - 1150. doi: 10.1111/j.1600-6143.2008.02236.x
https://ir.lib.uwo.ca/immunologypub/7
oai:ir.lib.uwo.ca:immunologypub-1006
2009-10-12T01:28:01Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
18566542
Receptor-interacting Protein-2 Deficiency Delays Macrophage Migration and Increases Intracellular Infection during Peritoneal Dialysis-associated Peritonitis
McCully, Michelle L.
Fairhead, Todd
Colmont, Chantal S.
Beasley, Federico C.
Heinrichs, David E.
Blake, Peter G.
Topley, Nicholas
Madrenas, Joaquín
Article
2008-10-01T07:00:00Z
Animals
Cell Movement
Cell-Free System
Humans
Infection
Inflammation
Macrophages
Mice
Mice
Transgenic
Models
Biological
Peritoneal Dialysis
Peritonitis
Receptor-Interacting Protein Serine-Threonine Kinase 2
Staphylococcus epidermidis
Time Factors
American Journal of Nephrology
American Journal of Nephrology
28
6
879
889
Immunology and Infectious Disease
Background: Early upregulation of receptor-interacting protein-2 (RIP2) expression during peritoneal dialysis (PD)-associated peritonitis correlates with a favorable clinical outcome, while failure to upregulate RIP2 correlates with a protracted course. We noticed that patients who do not upregulate RIP2 during PD-associated peritonitis have more peritoneal macrophages during the early phase of infection.
Methods: To study the mechanism behind this observation, we examined the role of RIP2 in the immune response to bacterial challenge in a mouse model of acute peritonitis. We injected RIP2(+/+) and RIP2(-/-) mice intraperitoneally with a Staphylococcus epidermidis cell free-preparation, and peritoneal cells were isolated 3, 6 and 24 h after challenge.
Results: Surprisingly, RIP2(-/-) mice had a comparable influx of inflammatory leukocytes, but had a significantly higher number of peritoneal macrophages at 3 h, indicating delayed emigration of these cells. No significant differences were seen at later times suggesting that migration was delayed but not inhibited. In addition, RIP2(-/-) macrophages were more permissive to intracellular infection by Staphylococcus aureus, indicating that, in the absence of RIP2, resident peritoneal macrophages could become reservoirs of bacteria.
Conclusion: These findings provide a mechanism for the observation that upregulation of RIP2 expression is required for rapid resolution of peritonitis, by decreasing intracellular infection and by regulating the migration of antigen-presenting cells in the early stages of an inflammatory response.
Published in: Am J Nephrol, 2008, 28:879-889. DOI: 10.1159/000141041
https://ir.lib.uwo.ca/immunologypub/6
oai:ir.lib.uwo.ca:immunologypub-1009
2011-10-25T05:12:32Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
17851464
Receptor-interacting Protein 2 Is a Marker for Resolution of Peritoneal Dialysis-associated Peritonitis
McCully, Michelle L.
Baroja, M. L.
Chau, T. A.
Jain, A. K.
Barra, L.
Salgado, A.
Blake, P. G.
Madrenas, Joaquin
Article
2007-11-01T07:00:00Z
Adult
Aged
Antigens
CD14
Biological Markers
Female
Humans
Interleukin-12 Subunit p35
Leukocytes
Mononuclear
Lipopolysaccharides
Male
Middle Aged
Peptidoglycan
Peritoneal Dialysis
Peritonitis
RNA
Messenger
Receptor-Interacting Protein Serine-Threonine Kinase 2
Teichoic Acids
Tetradecanoylphorbol Acetate
Toll-Like Receptor 2
Toll-Like Receptor 4
Up-Regulation
Kidney International
Kidney International
72
10
1273
1281
http://dx.doi.org/10.1159/000141041
Immunology and Infectious Disease
<p>There are no predictive factors for peritoneal dialysis-associated peritonitis; however, its resolution correlates with a cell-mediated Th1 immune response. We tested the hypothesis that induction of receptor-interacting protein 2 (RIP2), an assumed kinase linked with Th1 responses, is a useful marker in this clinical setting. Basal RIP2 expression was measured in human immune cells and during dialysis-associated peritonitis. RIP2 increased with bacterial toxin cell activation and the temporal profile for this differed depending on immune cell involvement in the innate or adaptive phases of the response. Importantly, RIP2 expression increased in peritoneal immune cells during dialysis-associated peritonitis and this upregulation correlated with clinical outcome. An early induction in peritoneal CD14(+) cells correlated with rapid resolution, whereas minimal induction correlated with protracted infection and with catheter loss in 36% of patients. These latter patients had higher levels of MCP-1 consistent with a delayed transition from innate to adaptive immunity. Our study shows that upregulation of RIP2 is a useful marker to monitor dialysis-associated peritonitis and in predicting the clinical outcome of these infections.</p>
https://ir.lib.uwo.ca/immunologypub/9
oai:ir.lib.uwo.ca:immunologypub-1008
2009-10-12T01:07:22Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
17785798
Molecular Determinants of Inverse Agonist Activity of Biologicals Targeting CTLA-4
Teft, Wendy A.
Madrenas, Joaquín
Article
2007-09-15T07:00:00Z
Antibodies
Bispecific
Antigens
CD
Antigens
CD80
Antigens
Differentiation
Cytoplasm
Dimerization
Doxycycline
Drug Delivery Systems
Growth Inhibitors
Humans
Jurkat Cells
Ligands
Lymphocyte Activation
Sequence Deletion
Signal Transduction
T-Lymphocytes
The Journal of Immunology
The Journal of Immunology
179
6
3631
3637
Immunology and Infectious Disease
Ligation of CD28 or CTLA-4 with some biologicals can activate T cells due to an unexpected superagonist or inverse agonist activity, respectively. The risk of such an outcome limits the therapeutic development of these reagents. Thus, identifying the molecular determinants of superagonist/inverse agonist properties for biologicals targeting costimulatory/inhibitory receptors has not only fundamental value but also important therapeutic implications. In this study, we show that ligation of CTLA-4 with either soluble B7.1 Ig (but not B7.2 Ig) or with a recombinant bispecific in-tandem single chain Fv known as 24:26 induces TCR-independent, T cell activation. Such an inverse agonist activity requires CD28 expression and high CTLA-4 expression and is not seen when CTLA-4 is ligated by membrane-bound B7.1 or B7.2. At the molecular level, the inverse agonist activity of B7.1 Ig or 24:26 correlates with their ability to induce the formation of unique dimer-based, CTLA-4 oligomers on the T cell surface and involves CTLA-4 signaling through its cytoplasmic domain. Our results provide a potential mechanism to explain and to predict inverse agonist activity for CTLA-4 ligands.
https://ir.lib.uwo.ca/immunologypub/8
oai:ir.lib.uwo.ca:immunologypub-1010
2009-10-12T22:31:54Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
17369705
T Cell Signalling Induced by Bacterial Superantigens
Bueno, Clara
Criado, Gabriel
McCormick, John K.
Madrenas, Joaquín
Article
2007-01-01T08:00:00Z
Animals
Antigens
CD28
Histocompatibility Antigens Class II
Humans
Lymphocyte Activation
Receptors
Antigen
T-Cell
Signal Transduction
Staphylococcus
Streptococcus
Superantigens
T-Lymphocytes
Chemical Immunology and Allergy
Chemical Immunology and Allergy
93
161
180
Immunology and Infectious Disease
Bacterial superantigens (SAgs) constitute a large family of bacterial toxins that share the capacity to induce massive activation of the human immune system. Such a feature is based on the ability of these toxins to activate T cells that express Beta-chains of the T cell antigen receptor (TCR) containing variable regions (V) coded by specific families of VBeta genes. In addition, bacterial SAgs bypass the need for processing by antigen-presenting cells by directly binding to major histocompatibility complex class II molecules on the surface of these cells. Emerging work indicates that bacterial SAgs utilize not only the canonical pathways of TCR-mediated T cell activation but also other pathways. Here, we review the structural information on recognition of bacterial SAgs by T cells, the TCR signalling induced by this recognition event, and the effector functions that this recognition triggers. We analyze experimental evidence suggesting the existence of alternative receptors and coreceptors for bacterial SAgs, and outline future challenges in the research with these toxins.
Published in: Chem Immunol Allergy, 2007, vol 93, pp 161-180. DOI: 10.1159/000100894
https://ir.lib.uwo.ca/immunologypub/10
oai:ir.lib.uwo.ca:immunologypub-1015
2009-10-12T23:32:06Z
publication:mnipub
publication:anatomy
publication:biophysicspub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:anatomypub
publication:med
publication:biophysics
publication:biochempub
publication:mni
publication:robarts
publication:biochem
publication:institutes
17095724
Wilms’ Tumor 1–Associating Protein Regulates the Proliferation of Vascular Smooth Muscle Cells
Small, Theodore W.
Bolender, Zuzana
Bueno, Clara
O'Neil, Caroline
Nong, Zengxuan
Rushlow, Walter
Rajakumar, Nagalingham
Kandel, Christopher
Strong, Jennifer
Madrenas, Joaquin
Pickering, J. Geoffrey
Article
2006-12-08T08:00:00Z
Angioplasty
Balloon
Animals
Aorta
Thoracic
Apoptosis
Carotid Artery Injuries
Carrier Proteins
Cell Division
Cell Line
DNA-Binding Proteins
Gene Silencing
Glycoproteins
Humans
Intercellular Signaling Peptides and Proteins
Male
Muscle
Smooth
Vascular
Nuclear Proteins
Rats
Rats
Inbred WKY
Rats
Sprague-Dawley
Transcription
Genetic
Up-Regulation
WT1 Proteins
Circulation Research
Circulation Research
99
12
1338
1346
Immunology and Infectious Disease
Medical Anatomy
Medical Biochemistry
Medical Biophysics
Smooth muscle cells (SMCs) are called on to proliferate during vascular restructuring but must return to a nonproliferative state if remodeling is to appropriately terminate. To identify mediators of the reacquisition of replicative quiescence, we undertook gene expression screening in a uniquely plastic human SMC line. As proliferating SMCs shifted to a contractile and nonproliferative state, expression of TIMP-3, Axl, and KIAA0098 decreased whereas expression of complement C1s, cathepsin B, cellular repressor of E1A-activated genes increased. Wilms' tumor 1-associating protein (WTAP), a nuclear constituent of unknown function, was also upregulated as SMCs became nonproliferative. Furthermore, WTAP in the intima of injured arteries was substantially upregulated in the late stages of repair. Introduction of WTAP complementary DNA into human SMCs inhibited their proliferation, with a corresponding decrease in DNA synthesis and an increase in apoptosis. Knocking down endogenous WTAP increased SMC proliferation, because of increased DNA synthesis and G(1)/S phase transition, together with reduced apoptosis. WTAP was found to associate with the Wilms' tumor-1 protein in human SMCs and WTAP overexpression inhibited the binding of WT1 to an oligonucleotide containing a consensus WT1 binding site, whereas WTAP knockdown accentuated this interaction. Expression of the WT1 target genes, amphiregulin and Bcl-2, was suppressed in WTAP-overexpressing SMCs and increased in WTAP-deficient SMCs. Moreover, exogenous amphiregulin rescued the antiproliferative effect of WTAP. These findings identify WTAP as a novel regulator of the cell cycle and cell survival and implicate a WTAP-WT1 axis as a novel pathway for controlling vascular SMC phenotype.
Published in: Circulation Research, 2006, 99:1338-1346. doi: 10.1161/01.RES.0000252289.79841.d3
https://ir.lib.uwo.ca/immunologypub/14
oai:ir.lib.uwo.ca:immunologypub-1012
2009-10-14T01:00:41Z
publication:immunologypub
publication:robarts
publication:institutes
Membrane Compartmentalization during T Cell Receptor Signalling and Immunological Synapse Formation
Kirchhof, M. G.
Madrenas, J.
Article
2006-04-01T08:00:00Z
T lymphocyte
T lymphocyte antigen receptor
Lipid raft
Cytoskeleton
Immunological synapse
Signal transduction
Inmunologia
Inmunologia
25
2
131
141
Immunology and Infectious Disease
The interaction between transmembrane proteins, lipids, and cytoskeletal components provides a framework for the compartmentalization of the cell surface. Intense research has focused on lipid rafts, the cholesterol-enriched membrane microdomains containing many signalling molecules. However, recent advances in
cellular and molecular imaging have challenged prevailing models on the role of these membrane microdomains in signal transduction and their biological significance in cell physiology. Using the T lymphocyte as an example, we review here some of the current developments in our understanding of compartmentalization of signalling. T cells are useful to study this issue given the confluence of knowledge about the morphology associated with early signalling, about the kinetics of antigen receptor engagement, and about the resulting events leading to activation of these cells. Specifically, activation of the T cell upon T cell receptor (TCR) engagement with specific peptide: major histocompatibility complex
(MHC) molecule complexes on the surface of antigen-presenting cells (APC) results in a coordinated redistribution of some cell
surface proteins into a morphological structure known as the immunological synapse (IS) within a timeline encompassing antigen receptor signalling. In the context of these events, we examine the potential interactions between cell surface receptors, protein-protein microclusters, and cytoskeletal networks that support the formation of TCR-dependent signalling units or signalosomes in signalling permissive environments.
https://ir.lib.uwo.ca/immunologypub/16
oai:ir.lib.uwo.ca:immunologypub-1013
2009-10-12T23:04:05Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
16551244
A Molecular Perspective of CTLA-4 Function
Teft, Wendy A.
Kirchhof, Mark G.
Madrenas, Joaquín
Article
2006-04-01T08:00:00Z
Amino Acid Sequence
Animals
Antigens
CD
Antigens
Differentiation
Biological Transport
Active
Dimerization
Evolution
Molecular
Humans
Ligands
Lymphocyte Activation
Models
Immunological
Molecular Biology
Molecular Sequence Data
Polymorphism
Genetic
Protein Structure
Quaternary
Sequence Homology
Amino Acid
Signal Transduction
T-Lymphocytes
Annual Review of Immunology
Annual Review of Immunology
24
65
97
Immunology and Infectious Disease
Within the paradigm of the two-signal model of lymphocyte activation, the interest in costimulation has witnessed a remarkable emergence in the past few years with the discovery of a large array of molecules that can serve this role, including some with an inhibitory function. Interest has been further enhanced by the realization of these molecules' potential as targets to modulate clinical immune responses. Although the therapeutic translation of mechanistic knowledge in costimulatory molecules has been relatively straightforward, the capacity to target their inhibitory counterparts has remained limited. This limited capacity is particularly apparent in the case of the cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), a major negative regulator of T cell responses. Because there have been several previous comprehensive reviews on the function of this molecule, we focus here on the physiological implications of its structural features. Such an exercise may ultimately help us to design immunotherapeutic agents that target CTLA-4.
Published in: Annual Review of Immunology, Vol. 24: 65-97. doi: 10.1146/annurev.immunol.24.021605.090535
https://ir.lib.uwo.ca/immunologypub/12
oai:ir.lib.uwo.ca:immunologypub-1011
2009-10-12T22:40:24Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
17117590
The Immunological Synapse as a Novel Therapeutic Target
Teft, Wendy A.
Madrenas, Joaquin
Article
2006-10-26T07:00:00Z
Antigen Presentation
Antigen-Presenting Cells
Drug Design
Epitopes
T-Lymphocyte
Humans
Lymphocyte Activation
Receptors
Antigen
T-Cell
Signal Transduction
Technology
Pharmaceutical
Current Opinion in Investigational Drugs
Current Opinion in Investigational Drugs
7
11
1008
1013
Immunology and Infectious Disease
The onset of adaptive immune responses includes the presentation of foreign antigenic peptides to T-cells, and the formation of a T-cell-antigen-presenting cell interface termed the immunological synapse (IS). Although the generation of a mature IS is thought to be the hallmark of T-cell activation, new evidence suggests that microclusters ofat signaling molecules at the periphery of the IS are responsible for initiating and maintaining T-cell activation while the core of the IS provides a platform for signal downregulation. In this context, costimulatory molecules and self-peptides contribute to sustain the signaling required for T-lymphocyte differentiation into effector cells. This review discusses these aspects in the identification of novel candidates for therapeutic modulation of immune responses.
https://ir.lib.uwo.ca/immunologypub/11
oai:ir.lib.uwo.ca:immunologypub-1014
2009-10-12T23:14:01Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
16538869
Dendritic Cells as Arbiters of Peritoneal Immune Responses
McCully, Michelle L.
Madrenas, Joaquín
Article
2006-01-01T08:00:00Z
Animals
Dendritic Cells
Humans
Immunity
Innate
Peritoneum
Peritoneal Dialysis International
Peritoneal Dialysis International
26
1
8
25
Immunology and Infectious Disease
During the past few years, there has been a substantial increase in the understanding of innate immunity. Dendritic cells are emerging as key players in the orchestration of this early phase of immune responses, with a role that will translate into the subsequent type of adaptive immune response against infection. Here we provide an overview of dendritic cell differentiation and function, with particular emphasis on those features unique to the immune defense of the peritoneal cavity and in the context of peritoneal dialysis-associated immune responses. The reader is referred to the primary references included in the accompanying list for specific details in this fascinating field.
https://ir.lib.uwo.ca/immunologypub/13
oai:ir.lib.uwo.ca:surgerypub-1017
2009-10-13T00:03:24Z
publication:mnipub
publication:patholpub
publication:surgerypub
publication:pmid
publication:immunologypub
publication:faculties
publication:pathol
publication:mni
publication:robarts
publication:surgery
publication:institutes
17082607
Double-Negative T Cells, Activated by Xenoantigen, Lyse Autologous B and T Cells Using a Perforin/Granzyme-Dependent, Fas-Fas Ligand-Independent Pathway
Zhang, Zhu-Xu
Ma, Yuexia
Wang, Hao
Arp, Jacqueline
Jiang, Jifu
Huang, Xuyan
He, Kathy M.
Garcia, Bertha
Madrenas, Joaquím
Zhong, Robert
Article
2006-11-15T08:00:00Z
Adoptive Transfer
Animals
Antigens
CD95
Antigens
Heterophile
B-Lymphocyte Subsets
Cell Communication
Cell Death
Coculture Techniques
Cytotoxicity
Immunologic
Fas Ligand Protein
Graft Survival
Granzymes
Heart Transplantation
Lymphocyte Activation
Membrane Glycoproteins
Mice
Mice
Inbred BALB C
Mice
Inbred C57BL
Mice
Knockout
Perforin
Pore Forming Cytotoxic Proteins
Rats
Rats
Inbred BN
Rats
Inbred Lew
Signal Transduction
Spleen
T-Lymphocyte Subsets
The Journal of Immunology
177
10
6920
6929
Immunology and Infectious Disease
Pathology
Surgery
The ability to control the response of B cells is of particular interest in xenotransplantation as Ab-mediated hyperacute and acute xenograft rejection are major obstacles in achieving long-term graft survival. Regulatory T cells have been proven to play a very important role in the regulation of immune responses to self or non-self Ags. Previous studies have shown that TCRalphabeta+CD3+CD4-CD8- (double-negative (DN)) T cells possess an immune regulatory function, capable of controlling antidonor T cell responses in allo- and xenotransplantation through Fas-Fas ligand interaction. In this study, we investigated the possibility that xenoreactive DNT cells suppress B cells. We found that DNT cells generated from wild-type C57BL/6 mice expressed B220 and CD25 after rat Ag stimulation. These xenoreactive B220+CD25+ DNT cells lysed activated, but not naive, B and T cells. This killing, which took place through cell-cell contact, required participation of adhesion molecules. Our results indicate that Fas ligand, TGF-beta, TNF-alpha, and TCR-MHC recognition was not involved in DNT cell-mediated syngenic cell killing, but instead this killing was mediated by perforin and granzymes. The xenoreactive DNT cells expressed high levels of granzymes in comparison to allo- or xenoreactive CD8+ T cells. Adoptive transfer of DNT cells in combination with early immune suppression by immunosuppressive analog of 15-deoxyspergualin, LF15-0195, significantly prolonged rat heart graft survival to 62.1 +/- 13.9 days in mice recipients. In conclusion, this study suggests that xenoreactive DNT cells can control B and T cell responses in perforin/granzyme-dependent mechanisms. DNT cells may be valuable in controlling B and T cell responses in xenotransplantation.
https://ir.lib.uwo.ca/surgerypub/18
oai:ir.lib.uwo.ca:mnipub-1011
2009-10-12T23:50:56Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:mni
publication:robarts
publication:institutes
17142758
Molecular Basis of TCR Selectivity, Cross-Reactivity, and Allelic Discrimination by a Bacterial Superantigen: Integrative Functional and Energetic Mapping of the SpeC-Vbeta2.1 Molecular Interface
Rahman, A. K. M. Nur-ur
Herfst, Christine A.
Moza, Beenu
Shames, Stephanie R.
Chau, Luan A.
Bueno, Clara
Madrenas, Joaquín
Sundberg, Eric J.
McCormick, John K.
Article
2006-12-15T08:00:00Z
Alleles
Amino Acids
Bacterial Proteins
Binding Sites
Cell Line
Cross Reactions
Epitopes
Exotoxins
Humans
Jurkat Cells
Mutagenesis
Site-Directed
Protein Interaction Mapping
Receptors
Antigen
T-Cell
alpha-beta
Superantigens
Surface Plasmon Resonance
T-Cell Antigen Receptor Specificity
The Journal of Immunology
The Journal of Immunology
177
12
8595
8603
Immunology and Infectious Disease
Microbiology
Superantigens activate large fractions of T cells through unconventional interactions with both TCR beta-chain V domains (Vbetas) and MHC class II molecules. The bacterial superantigen streptococcal pyrogenic exotoxin C (SpeC) primarily stimulates human Vbeta2(+) T cells. Herein, we have analyzed the SpeC-Vbeta2.1 interaction by mutating all SpeC residues that make contact with Vbeta2.1 and have determined the energetic and functional consequences of these mutations. Our comprehensive approach, including mutagenesis, functional readouts from both bulk T cell populations, and an engineered Vbeta2.1(+) Jurkat T cell, as well as surface plasmon resonance binding analysis, has defined the SpeC "functional epitope" for TCR engagement. Although only two SpeC residues (Tyr(15) and Arg(181)) are critical for activation of virtually all human CD3(+) T cells, a larger cluster of four hot spot residues are required for interaction with Vbeta2.1. Three of these residues (Tyr(15), Phe(75), and Arg(181)) concentrate their binding energy on the CDR2 loop residue Ser(52a), a noncanonical residue insertion found only in Vbeta2 and Vbeta4 chains. Plasticity of this loop is important for recognition by SpeC. Although SpeC interacts with the Vbeta2.1 hypervariable CDR3 loop, our data indicate these contacts have little to no influence on the functional interaction with Vbeta2.1. These studies also provide a molecular basis for selectivity and cross-reactivity of SpeC-TCR recognition and reveal a degree of fine specificity in these interactions, whereby certain SpeC mutants are capable of distinguishing between different alleles of the same Vbeta domain subfamily.
https://ir.lib.uwo.ca/mnipub/12
oai:ir.lib.uwo.ca:immunologypub-1016
2009-10-13T00:11:27Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:mni
publication:robarts
publication:institutes
16887985
FcR{gamma} Presence in TCR Complex of Double-Negative T Cells Is Critical for Their Regulatory Function
Thomson, Christopher W.
Teft, Wendy A.
Chen, Wenhao
Lee, Boris P.-L.
Madrenas, Joaquin
Zhang, Li
Article
2006-08-15T07:00:00Z
Animals
Cell Line
Clone Cells
Mice
Mice
Inbred BALB C
Mice
Inbred C57BL
Mice
Knockout
Mice
Transgenic
Receptors
Antigen
T-Cell
Receptors
IgG
Skin Transplantation
T-Lymphocytes
Regulatory
The Journal of Immunology
The Journal of Immunology
177
4
2250
2257
Immunology and Infectious Disease
TCRalphabeta+CD4-CD8- double-negative (DN) T regulatory (Treg) cells have recently been shown to suppress Ag-specific immune responses mediated by CD8+ and CD4+ T cells in humans and mice. Our previous study using cDNA microarray analysis of global gene expression showed that FcRgamma was the most highly overexpressed gene in functional DN Treg cell clones compared with nonfunctional mutant clones. In this study, we demonstrate that FcRgamma-deficient DN T cells display markedly reduced suppressive activity in vitro. In addition, unlike FcRgamma-sufficient DN T cells, FcRgamma-deficient DN T cells were unable to prolong donor-specific allograft survival when adoptively transferred to recipient mice. Protein analyses indicate that in addition to FcRgamma, DN Treg cell clones also express higher levels of TCRbeta, while mutant clones expressed higher levels of Zap70 and Lck. Within DN Treg cells, we found that FcRgamma associates with the TCR complex and that both FcRgamma and Syk are phosphorylated in response to TCR cross-linking. Inhibition of Syk signaling and FcRgamma expression were both found to reduce the suppressive function of DN Treg cells in vitro. These results indicate that FcRgamma deficiency significantly impairs the ability of DN Treg cells to down-regulate allogeneic immune responses both in vitro and in vivo, and that FcRgamma plays a role in mediating TCR signaling in DN Treg cells.
https://ir.lib.uwo.ca/immunologypub/15
oai:ir.lib.uwo.ca:immunologypub-1017
2009-10-14T01:42:55Z
publication:mnipub
publication:physpharmpub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:physpharm
publication:mni
publication:robarts
publication:institutes
16860758
Bacterial Superantigens Bypass Lck-Dependent T Cell Receptor Signaling by Activating a Gα11-Dependent, PLC-β-Mediated Pathway
Bueno, Clara
Lemke, Caitlin D.
Criado, Gabriel
Baroja, Miren L.
Ferguson, Stephen S. G.
Rahman, A. K. M. Nur-Ur
Tsoukas, Constantine D.
McCormick, John K.
Madrenas, Joaquin
Article
2006-07-01T07:00:00Z
Antigens
Bacterial
Antigens
CD4
Calcium
Cells
Cultured
Enterotoxins
Enzyme Activation
Extracellular Signal-Regulated MAP Kinases
GTP-Binding Protein alpha Subunits
Gq-G11
Humans
Interleukin-2
Isoenzymes
Lymphocyte Activation
Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
Phospholipase C beta
Phosphoserine
Protein Kinase C
Receptors
Antigen
T-Cell
Signal Transduction
Superantigens
Type C Phospholipases
Immunity
Immunity
25
1
67
78
Immunology and Infectious Disease
Medical Physiology
The paradigm to explain antigen-dependent T cell receptor (TCR) signaling is based on the activation of the CD4 or CD8 coreceptor-associated kinase Lck. It is widely assumed that this paradigm is also applicable to signaling by bacterial superantigens. However, these bacterial toxins can activate human T cells lacking Lck, suggesting the existence of an additional pathway of TCR signaling. Here we showed that this alternative pathway operates in the absence of Lck-dependent tyrosine-phosphorylation events and was initiated by the TCR-dependent activation of raft-enriched heterotrimeric Galpha11 proteins. This event, in turn, activated a phospholipase C-beta and protein kinase C-mediated cascade that turned on the mitogen-activated protein kinases ERK-1 and ERK-2, triggered Ca(2+) influx, and translocated the transcription factors NF-AT and NF-kappaB to the nucleus, ultimately inducing the production of interleukin-2 in Lck-deficient T cells. The triggering of this alternative pathway by superantigens suggests that these toxins use a G protein-coupled receptor as a coreceptor on T cells.
Published in: Immunity, Volume 25, Issue 1, 67-78, 1 July 2006. doi: 10.1016/j.immuni.2006.04.012
https://ir.lib.uwo.ca/immunologypub/17
oai:ir.lib.uwo.ca:surgerypub-1018
2011-05-29T22:38:45Z
publication:mnipub
publication:patholpub
publication:surgerypub
publication:pmid
publication:immunologypub
publication:faculties
publication:pathol
publication:mni
publication:robarts
publication:surgery
publication:institutes
16539628
A Synergistic Effect Between PG490-88 and Tacrolimus Prolongs Renal Allograft Survival in Monkeys
Chen, G.
Sun, H.
Arp, J.
Garcia, B.
Wang, X.
Wise, Y.
Liu, W.
Ramcharran, S.
Huang, X.
Xiang, Y.
Yang, H.
Fang, Z.
Madrenas, J.
Sudo, Y.
Tamura, K.
Zhong, R.
Article
2006-04-01T08:00:00Z
Animals
Cell Proliferation
Diterpenes
Drug Synergism
Graft Rejection
Graft Survival
Haplorhini
Immunoglobulin M
Immunosuppressive Agents
Interferon-gamma
Interleukin-2
Kidney Transplantation
Male
NF-kappa B
NFATC Transcription Factors
T-Lymphocytes
Tacrolimus
Transcriptional Activation
American Journal of Transplantation
6
4
714
723
http://dx.doi.org/10.1111/j.1600-6143.2006.01257.x
Allergy and Immunology
Pathology
Surgery
<p>This study was undertaken to determine if PG490-88 and tacrolimus (Tac) act synergistically to prevent renal allograft rejection in monkeys and to explore possible mechanisms of synergy between these agents. MHC-mismatched renal allografts were transplanted into cynomolgus monkeys after bilateral nephrectomy. Recipients were divided into the following groups: (i) no treatment; (ii) PG490-88 (0.03 mg/kg); (iii) Tac (1 mg/kg); (iv) PG490-88 (0.01 mg/kg) + Tac (1 mg/kg) and (v) PG490-88 (0.03 mg/kg) + Tac (1 mg/kg). Through synergy PG490-88 and Tac inhibited anti-CD3/PMA-induced T-cell proliferation and IFN-gamma expression in vitro. Tac monotherapy only marginally prolonged survival (27 +/- 3.2 days), while the combination of PG490-88 and Tac significantly prolonged graft survival to a median of 99 days (PG490-88 at 0.03 mg) and 38.5 days (PG490-88 at 0.01 mg/kg). Prolonged survival correlated with inhibited IgM production as well as reduced T-cell infiltration, IL-2 protein expression and NF-AT/NF-kappaB activity. We conclude that PG490-88 and a subtherapeutic dose of Tac significantly prolong renal allograft survival in monkeys through the synergistic inhibition of T-cell activation and a decrease in IFN-gamma production and NF-AT/NF-kappaB activity.</p>
https://ir.lib.uwo.ca/surgerypub/19
oai:ir.lib.uwo.ca:immunologypub-1018
2009-10-19T23:44:28Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
16301324
Complement Regulatory Protein Crry/p65-mediated Signaling in T Lymphocytes: Role of Its Cytoplasmic Domain and Partitioning into Lipid Rafts
Jiménez-Periañez, Arturo
Ojeda, Gloria
Criado, Gabriel
Sánchez, Alejandra
Pini, Eliana
Madrenas, Joaquín
Rojo, Jose Maria
Portolés, Pilar
Article
2005-12-01T08:00:00Z
Animals
Antigens
CD3
Cell Line
Cytoplasm
Extracellular Signal-Regulated MAP Kinases
Immunity
Innate
JNK Mitogen-Activated Protein Kinases
Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
Membrane Microdomains
Mice
Oncogene Protein v-akt
Protein Structure
Tertiary
Proto-Oncogene Proteins c-vav
Receptors
Complement
Signal Transduction
T-Lymphocytes
Th1 Cells
ZAP-70 Protein-Tyrosine Kinase
p38 Mitogen-Activated Protein Kinases
Journal of Leukocyte Biology
Journal of Leukocyte Biology
78
6
1386
1396
Immunology and Infectious Disease
Crry/p65 is a type I glycoprotein, which protects mouse T cells from complement attack. We have previously shown that complement receptor I-related protein Crry/p65 (Crry) ligation has a costimulatory effect on mouse CD4+ T cell activation. Here, we have examined the mechanisms responsible for Crry costimulation, addressing the question of whether Crry potentiates signal transduction starting at the T cell receptor (TCR)/CD3 complex or promotes distinct costimulatory signals. We show that Crry increases early TCR-dependent activation signals, including p56lck-, zeta-associated protein-70 (ZAP-70), Vav-1, Akt, and extracellular signal-regulated kinase (ERK) phosphorylation but also costimulation-dependent mitogen-activated protein kinases (MAPK), such as the stress-activated c-Jun N-terminal kinase (JNK). It is intriguing that Crry costimulus enhanced p38 MAPK activation in T helper cell type 1 (Th1) but not in Th2 cells. A fraction of Crry is found consistently in the detergent-insoluble membrane fraction of Th1 or Th2 cells or CD4+ lymphoblasts. Crry costimulation induced clustering of lipid rafts, increasing their content in Crry, CD3epsilon, and p59-60 forms of p56lck, and caused actin polymerization close to the site of activation in Th2 cells. Such events were inhibited by wortmannin, suggesting a role for phosphatidylinositol-3 kinase in these effects. The Crry cytoplasmic domain was required for JNK activation and interleukin-4 secretion but not for the presence of Crry in rafts or activation of p56lck, ZAP-70, Akt, Vav-1, or ERK. This suggests that Crry costimulation involves two different but not mutually exclusive signal transduction modules. The dual function of Crry as a complement regulatory protein and as a T cell costimulator illustrates the importance of complement regulatory proteins as links between innate and adaptive immunity.
Published in: Journal of Leukocyte Biology. 2005;78:1386-1396. doi: 10.1189/jlb.1104642
https://ir.lib.uwo.ca/immunologypub/18
oai:ir.lib.uwo.ca:immunologypub-1019
2009-10-19T23:55:03Z
publication:mnipub
publication:hismed
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:hismedpub
publication:med
publication:mni
publication:robarts
publication:institutes
publication:campusunits
16360794
Giving Credit Where Credit Is Due: John Hunter and the Discovery of Erythrocyte Sedimentation Rate
Madrenas, Joaquín
Potter, Paul
Cairns, Ewa
Article
2005-12-17T08:00:00Z
Blood Sedimentation
Great Britain
History
18th Century
The Lancet
The Lancet
366
9503
2140
2141
Immunology and Infectious Disease
Published in: The Lancet, Volume 366, Issue 9503, Pages 2140 - 2141, 17 December 2005. doi: 10.1016/S0140-6736(05)67337-0
https://ir.lib.uwo.ca/immunologypub/19
oai:ir.lib.uwo.ca:immunologypub-1020
2009-11-29T09:58:43Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
16136471
Virus Attachment and Replication Are Promoted after Acquisition of Host CD28 and CD152 by HIV-1
Giguere, Jean-Francois
Diou, Juliette
Madrenas, Joaquim
Tremblay, Michel J.
Article
2005-10-01T07:00:00Z
Antigens
CD
Antigens
CD28
Antigens
Differentiation
Down-Regulation
HIV-1
Humans
Jurkat Cells
Up-Regulation
Virion
Journal of Infectious Diseases
Journal of Infectious Diseases
192
7
1265
1268
10.1086/444426
Immunology and Infectious Disease
CD28 is constitutively expressed on CD4(+) cells, but its homologue CD152 is only weakly expressed after cell activation. To determine whether these 2 costimulatory molecules can be inserted into human immunodeficiency virus type 1 (HIV-1), virus was produced in CD28- and CD152-expressing Jurkat-derived cells. Both molecules were efficiently acquired by virions. Virus attachment and infectivity were more affected by CD152 than by CD28. Given that CD28/CD152-CD80/CD86 interactions play a dominant role in antigen presentation, it can thus be proposed that the association between virus-anchored host CD28/CD152 and cell-surface CD80/CD86 on target cells might have consequences for the transmission and pathogenesis of HIV-1.
https://ir.lib.uwo.ca/immunologypub/20
oai:ir.lib.uwo.ca:immunologypub-1021
2009-11-29T10:05:18Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
16002699
Hierarchical Regulation of CTLA-4 Dimer-based Lattice Formation and its Biological Relevance for T cell Inactivation
Darlington, Peter J.
Kirchhof, Mark G.
Criado, Gabriel
Sondhi, Jitin
Madrenas, Joaquín
Article
2005-07-15T07:00:00Z
Alanine
Antigens
CD
Antigens
CD80
Antigens
CD86
Antigens
Differentiation
Cell Line
Transformed
Cysteine
Dimerization
Disulfides
Glycosylation
Humans
Immunosuppressive Agents
Jurkat Cells
Ligands
Lymphocyte Activation
Membrane Glycoproteins
Membrane Microdomains
Point Mutation
Protein Binding
T-Lymphocytes
Journal of Immunology
Journal of Immunology
175
2
996
1004
Immunology and Infectious Disease
CTLA-4 is an activation-induced, homodimeric inhibitory receptor in T cells. Recent crystallographic reports have suggested that it may form lattice-like arrays on the cell surface upon binding B7.1/B7.2 (CD80, CD86) molecules. To test the biological relevance of these CTLA-4-B7 lattices, we introduced a C122A point mutation in human CTLA-4, because this residue was shown to be essential for dimerization in solution. Surprisingly, we found that up to 35% of C122A CTLA-4 dimerized in human T lymphocytes. Moreover, C122A CTLA-4 partitioned within lipid rafts, colocalized with the TCR in the immunological synapse, and inhibited T cell activation. C122-independent dimerization of CTLA-4 involved N-glycosylation, because further mutation of the N78 and N110 glycosylation sites abrogated dimerization. Despite being monomeric, the N78A/N110A/C122A triple mutant CTLA-4 localized in the immunological synapse and inhibited T cell activation. Such functionality correlated with B7-induced dimerization of these mutant molecules. Based on these data, we propose a model of hierarchical regulation of CTLA-4 oligomerization by which B7 binding ultimately determines the formation of dimer-dependent CTLA-4 lattices that may be necessary for triggering B7-dependent T cell inactivation.
https://ir.lib.uwo.ca/immunologypub/21
oai:ir.lib.uwo.ca:immunologypub-1022
2009-11-29T10:14:22Z
publication:mnipub
publication:surgerypub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:surgery
publication:institutes
15730398
Characterization of Human Peritoneal Dendritic Cell Precursors and Their Involvement in Peritonitis
McCully, M. L.
Chau, T. A.
Luke, P.
Blake, P. G.
Madrenas, J.
Article
2005-03-01T08:00:00Z
Adult
Aged
Analysis of Variance
Antigens
CD14
Case-Control Studies
Cell Differentiation
Cytokines
Dendritic Cells
Endocytosis
Female
Flow Cytometry
Humans
Immunophenotyping
Lymphocyte Count
Macrophages
Male
Microscopy
Confocal
Middle Aged
Peritoneal Dialysis
Peritoneum
Peritonitis
Th1 Cells
Clinical and Experimental Immunology
Clinical and Experimental Immunology
139
3
513
525
10.1111/j.1365-2249.2005.02713.x
Immunology and Infectious Disease
Scattered evidence suggests that the human peritoneal cavity contains cells of the dendritic cell (DC) lineage but their characterization is missing. Here, we report that the peritoneal cavity of normal subjects and of stable patients on peritoneal dialysis (PD) contains a population of CD14(+) cells that can differentiate into DCs or macrophages. Within this pool, we characterized a CD14(+)CD4(+) cell subset (2.2% of the peritoneal cells) fulfilling the definition of myeloid DC precursors or pre-DC1 cells. These cells expressed high levels of HLA-DR, CD13, CD33, and CD86, and low levels of CD40, CD80, CD83, CD123, CD209, TLR-2 and TLR-4. These cells retained CD14 expression until late stages of differentiation, despite concomitant up-regulation of DC-SIGN (CD209), CD1a, CD80 and CD40. Peritoneal pre-DC1 cells had endocytic capacity that was down-regulated upon LPS/IFN-gamma stimulation, were more potent allo-stimulators than peritoneal CD14(+)CD4(-/lo) cells and monocyte-derived macrophages, and induced Th1 cytokine responses. More importantly, the number of peritoneal pre-DC1 cells increased during PD-associated peritonitis, with a different profile for Gram positive and Gram negative peritonitis, suggesting that these cells participate in the induction of peritoneal adaptive immune responses, and may be responsible for the bias towards Th1 responses during peritonitis.
https://ir.lib.uwo.ca/immunologypub/22
oai:ir.lib.uwo.ca:immunologypub-1026
2009-11-29T10:26:07Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
15495162
Mechanism of Modulation of T Cell Responses by N-palmitoylated Peptides
Bueno, Clara
Lee, Kenneth K.
Chau, Luan A.
Lee-Chan, Edwin
Singh, Bhagirath
Strejan, Gill H.
Madrenas, Joaquín
Article
2004-12-01T08:00:00Z
Animals
Female
Immune Tolerance
Mice
Palmitic Acid
Peptide Fragments
Receptors
Antigen
T-Cell
Signal Transduction
T-Lymphocytes
European Journal of Immunology
European Journal of Immunology
34
12
3497
3507
10.1002/eji.200425369
Immunology and Infectious Disease
Small structural changes in the antigenic peptides recognized by TCR can alter the biological properties of those peptides and convert them into weak agonists, partial agonists, or antagonists of these receptors. These altered peptide ligands (APL) are usually generated by conservative amino acid substitutions at TCR contact residues. Here, we show that APL with therapeutic properties can also be generated by attachment of palmitic acid at the N terminus of the peptide without the need to modify the peptide's primary sequence. Using N-palmitoylated pigeon cytochrome-c peptide 81-104 (PALPCC(81-104)), we were able to induce T cell hyporesponsiveness to the wild-type peptide in vitro. More importantly, administration of the PALPCC(81-104 )to mice reduced the responsiveness to the native peptide when tested ex vivo. Biochemical and functional experiments indicated that the action of N-palmitoylated peptides was due to the conversion of the native peptide into a weak agonist that could then induce T cell anergy. Our results demonstrate that N-palmitoylation of antigenic peptides is a feasible strategy to generate APL, as it avoids the need to screen multiple amino acid variants of each specific antigen to identify those with therapeutic properties.
https://ir.lib.uwo.ca/immunologypub/24
oai:ir.lib.uwo.ca:immunologypub-1023
2009-11-29T10:19:41Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
15585310
Polycationic Lipids Inhibit the Pro-inflammatory Response to LPS
Leon-Ponte, Matilde
Kirchhof, Mark G.
Sun, Tina
Stephens, Tracey
Singh, Bhagirath
Sandhu, Shabaz
Madrenas, Joaquín
Article
2005-01-15T08:00:00Z
Animals
Antigens
CD14
Cations
Cytokines
Flow Cytometry
Immune System
Immune Tolerance
Lipids
Lipopolysaccharides
Membrane Glycoproteins
Mice
Mice
Inbred BALB C
Microscopy
Confocal
Mitogen-Activated Protein Kinases
Receptors
Cell Surface
Toll-Like Receptor 4
Toll-Like Receptors
Immunology Letters
Immunology Letters
96
1
73
83
10.1016/j.imlet.2004.07.019
Immunology and Infectious Disease
Lipopolysaccharide (LPS) is a major component of the outer membrane of Gram-negative bacteria. As such, it signals monocytes, macrophages and neutrophils to up-regulate phagocytic functions and to release pro-inflammatory cytokines. Despite the established role of CD14 as the main LPS receptor, the precise nature of the LPS signalling complex and its compartmentalization remain unknown. Interactions of LPS with other cell surface molecules such as TLR-4 and MD-2, and its subsequent internalization are required for LPS signalling. Here, we show that the polycationic lipid LipoFectamine causes inhibition of the LPS-induced MAPK activation and lack of pro-inflammatory cytokine production, despite proper localization of CD14 within lipid rafts and massive LPS internalization. The ability of LipoFectamine to inhibit LPS induced pro-inflammatory responses may be due to uncoupling of CD14 from TLR-4/MD-2 in the LPS signalling complex of mouse macrophages/microglial cells, as suggested by inhibition of LPS-induced concomitant internalization of these surface molecules. Thus, LipoFectamine may be a useful tool to dissect the molecular interactions leading to LPS signalling, and identifies a potential therapeutic strategy for LPS clearance.
https://ir.lib.uwo.ca/immunologypub/23
oai:ir.lib.uwo.ca:immunologypub-1025
2010-01-25T01:09:39Z
publication:mnipub
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
Lymphocytes: Antigen-induced Gene Activation
Criado, Gabriel
Madrenas, Joaquín
Article
2005-01-01T08:00:00Z
10.1038/npg.els.0004033
Immunology and Infectious Disease
Lymphocytes are activated upon antigen recognition by their clone-specific surface antigen receptors. Lymphocyte activation includes multiple signalling cascades that converge in the cell nucleus to cause significant changes in the pattern of gene expression that determine the phenotype of activated lymphocytes and ultimately, the type of immune response.
Published as an article in: <em>Encyclopedia of Life Sciences</em>.
https://ir.lib.uwo.ca/immunologypub/80
oai:ir.lib.uwo.ca:immunologypub-1027
2010-11-17T00:20:10Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
15277692
Human Embryonic Stem Cells Possess Immune-privileged Properties
Li, Li
Baroja, Miren L.
Majumdar, Anish
Chadwick, Kristin
Rouleau, Anne
Gallacher, Lisa
Ferber, Iris
Lebkowski, Jane
Martin, Tanya
Madrenas, Joaquin
Bhatia, Mickie
Article
2004-07-01T07:00:00Z
Animals
Cell Differentiation
Cell Line
Tumor
Dendritic Cells
Embryo
Mammalian
Graft Rejection
Humans
Major Histocompatibility Complex
Mice
Stem Cells
T-Lymphocytes
Transplantation Immunology
Transplantation
Heterologous
Stem Cells
Stem Cells
22
4
448
456
http://dx.doi.org/10.1634/stemcells.22-4-448
Immunology and Infectious Disease
Human embryonic stem cells (hESCs) are envisioned to be a major source for cell-based therapies. Efforts to overcome rejection of hESCs include nuclear transfer and collection of hESC banks representing the broadest diversity of major histocompatability complex (MHC) polymorphorisms. Surprisingly, immune responses to hESCs have yet to be experimentally evaluated. Here, injection of hESCs into immune-competent mice was unable to induce an immune response. Undifferentiated and differentiated hESCs failed to stimulate proliferation of alloreactive primary human T cells and inhibited third-party allogeneic dendritic cell-mediated T-cell proliferation via cellular mechanisms independent of secreted factors. Upon secondary rechallenge, T cells cocultured with hESCs were still responsive to allogeneic stimulators but failed to proliferate upon re-exposure to hESCs. Our study demonstrates that hESCs possess unique immune-privileged characteristics and provides an unprecedented opportunity to further investigate the mechanisms of immune response to transplantation of hESCs that may avoid immune-mediated rejection.
https://ir.lib.uwo.ca/immunologypub/25
oai:ir.lib.uwo.ca:immunologypub-1029
2009-11-29T10:39:39Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
15128776
Conversion of CTLA-4 from Inhibitor to Activator of T cells with a Bispecific Tandem Single-chain Fv Ligand
Madrenas, Joaquín
Chau, Luan A.
Teft, Wendy A.
Wu, Paul W.
Jussif, Jason
Kasaian, Marion
Carreno, Beatriz M.
Ling, Vincent
Article
2004-05-15T07:00:00Z
Adjuvants
Immunologic
Antibodies
Bispecific
Antigens
CD
Antigens
CD28
Antigens
Differentiation
Binding Sites
Antibody
Enzyme Activation
Humans
Immunoconjugates
Immunoglobulin Fragments
Jurkat Cells
Ligands
Lymphocyte Activation
Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
Phosphoprotein Phosphatases
Protein Phosphatase 2
Receptor-CD3 Complex
Antigen
T-Cell
Signal Transduction
Suppressor Factors
Immunologic
T-Lymphocyte Subsets
Journal of Immunology
Journal of Immunology
172
10
5948
5956
Immunology and Infectious Disease
Abs or their recombinant fragments against surface receptors of the Ig superfamily can induce or block the receptors' native function depending on whether they induce or prevent the assembly of signalosomes on their cytoplasmic tails. In this study, we introduce a novel paradigm based on the observation that a bispecific tandem single-chain variable region fragment ligand of CTLA-4 by itself converts this inhibitory receptor into an activating receptor for primary human T lymphocytes. This reversal of function results from increased recruitment of the serine/threonine phosphatase 2A to the cytoplasmic tail of CTLA-4, consistent with a role of this phosphatase in the regulation of CTLA-4 function, and assembly of a distinct signalosome that activates an lck-dependent signaling cascade and induces IL-2 production. Our data demonstrate that the cytoplasmic domain of CTLA-4 has an inherent plasticity for signaling that can be exploited therapeutically with recombinant ligands for this receptor.
https://ir.lib.uwo.ca/immunologypub/27
oai:ir.lib.uwo.ca:immunologypub-1028
2009-11-29T10:34:30Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
15163715
Insertion of Host-derived Costimulatory Molecules CD80 (B7.1) and CD86 (B7.2) into Human Immunodeficiency Virus Type 1 affects the Virus Life Cycle
Giguère, Jean-François
Bounou, Salim
Paquette, Jean-Sébastien
Madrenas, Joaquín
Tremblay, Michel J.
Article
2004-06-01T07:00:00Z
Antigens
CD
Antigens
CD28
Antigens
CD3
Antigens
CD80
Antigens
CD86
Antigens
Differentiation
Cell Line
HIV-1
Humans
Jurkat Cells
Macrophages
Membrane Glycoproteins
NF-kappa B
T-Lymphocytes
Virion
Virus Replication
Journal of Virology
Journal of Virology
78
12
6222
6232
10.1128/JVI.78.12.6222-6232.2004
Immunology and Infectious Disease
Human immunodeficiency virus type 1 (HIV-1) carries virus-encoded and host-derived proteins. Recent advances in the functional characterization of host molecules inserted into mature virus particles have revealed that HIV-1 biology is influenced by the acquisition of host cell membrane components. The CD28/B7 receptor/ligand system is considered one of the fundamental elements of the normal immune response. Two major cell types that harbor HIV-1 in vivo, i.e., monocytes/macrophages and CD4+ T cells, express the costimulatory molecules CD80 (B7.1) and CD86 (B7.2). We investigated whether CD80 and CD86 are efficiently acquired by HIV-1, and if so, whether these host-encoded molecules can contribute to the virus life cycle. Here we provide the first evidence that the insertion of CD80 and CD86 into HIV-1 increases virus infectivity by facilitating the attachment and entry process due to interactions with their two natural ligands, CD28 and CTLA-4. Moreover, we demonstrate that NF-kappaB is induced by CD80- and CD86-bearing virions when they are combined with the engagement of the T-cell receptor/CD3 complex, an event that is inhibited upon surface expression of CTLA-4. Finally, both CD80 and CD86 were found to be efficiently incorporated into R5- and X4-tropic field strains of HIV-1 expanded in cytokine-treated macrophages. Thus, besides direct interactions between the virus envelope glycoproteins and cell surface constituents, such as CD4 and some specific chemokine coreceptors, HIV-1 may attach to target cells via interactions between cell-derived molecules incorporated into virions and their natural ligands. These findings support the theory that HIV-1-associated host proteins alter virus-host dynamics.
https://ir.lib.uwo.ca/immunologypub/26
oai:ir.lib.uwo.ca:immunologypub-1031
2009-11-29T10:48:24Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
14688329
Superantigen Stimulation Reveals the Contribution of Lck to Negative Regulation of T Cell Activation
Criado, Gabriel
Madrenas, Joaquín
Article
2004-01-01T08:00:00Z
Cell Line
Cell Line
Transformed
Cytokines
DNA-Binding Proteins
Down-Regulation
Enterotoxins
Humans
Jurkat Cells
Lymphocyte Activation
Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
Membrane Proteins
NFATC Transcription Factors
Nuclear Proteins
Pyrimidines
Receptors
Antigen
T-Cell
Signal Transduction
Staphylococcus aureus
Superantigens
T-Lymphocytes
Transcription Factors
Journal of Immunology
Journal of Immunology
172
1
222
230
Immunology and Infectious Disease
The conventional paradigm of T cell activation through the TCR states that Lck plays a critical activating role in this signaling process. However, the T cell response to bacterial superantigens does not require Lck. In this study we report that not only is Lck dispensable for T cell activation by superantigens, but it actively inhibits this signaling pathway. Disruption of Lck function, either by repression of Lck gene expression or by selective pharmacologic inhibitors of Lck, led to increased IL-2 production in response to superantigen stimulation. This negative regulatory effect of Lck on superantigen-induced T cell responses required the kinase activity of Lck and correlated with early TCR signaling, but was independent of immunological synapse formation and TCR internalization. Our data demonstrate that the multistage role of Lck in T cell signaling includes the activation of a negative regulatory pathway of T cell activation.
https://ir.lib.uwo.ca/immunologypub/29
oai:ir.lib.uwo.ca:immunologypub-1030
2009-11-29T10:44:22Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
14734719
Lck is Required for Activation-induced T Cell Death after TCR Ligation with Partial Agonists
Yu, Xue-Zhong
Levin, Steven D.
Madrenas, Joaquin
Anasetti, Claudio
Article
2004-02-01T08:00:00Z
Amino Acid Sequence
Animals
Antibodies
Monoclonal
Antigens
Antigens
CD3
Antigens
CD95
Apoptosis
Calcium
Cells
Cultured
Enzyme Activation
Fas Ligand Protein
Immunoglobulin Fab Fragments
Ligands
Lymphocyte Activation
Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
Membrane Glycoproteins
Mice
Mice
Inbred BALB C
Mice
Inbred C57BL
Mice
Inbred MRL lpr
Mice
Knockout
Mice
Transgenic
Mitogen-Activated Protein Kinases
Molecular Sequence Data
NF-kappa B
Ovalbumin
Peptide Fragments
Proto-Oncogene Proteins
Proto-Oncogene Proteins c-fos
Proto-Oncogene Proteins c-fyn
Receptors
Antigen
T-Cell
Solubility
T-Lymphocyte Subsets
Up-Regulation
src-Family Kinases
Journal of Immunology
Journal of Immunology
172
3
1437
1443
Immunology and Infectious Disease
Oncology
TCR engagement can induce either T cell proliferation and differentiation or activation-induced T cell death (AICD) through apoptosis. The intracellular signaling pathways that dictate such a disparate fate after TCR engagement have only been partially elucidated. Non-FcR-binding anti-CD3 mAbs induce a partial agonist TCR signaling pattern and cause AICD on Ag-activated, cycling T cells. In this study, we examined TCR signaling during the induction of AICD by anti-CD3 fos, a non-FcR-binding anti-CD3 mAb. This mAb activates Fyn, Lck, and extracellular signal-regulated kinase, and induces phosphorylation of Src-like adapter protein, despite the inability to cause calcium mobilization or TCR polarization. Anti-CD3 fos also fails to effectively activate zeta-associated protein of 70 kDa or NF-kappaB. Using Ag-specific T cells deficient for Fyn or Lck, we provide compelling evidence that activation of Lck is required for the induction of AICD. Our data indicate that a selective and distinct TCR signaling pattern is required for AICD by TCR partial agonist ligands.
https://ir.lib.uwo.ca/immunologypub/28
oai:ir.lib.uwo.ca:immunologypub-1032
2009-11-29T10:55:52Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
12972512
TCR Subunit Specificity of CTLA-4-mediated Signaling
Siu, Eric
Carreno, Beatriz M.
Madrenas, Joaquín
Article
2003-12-01T08:00:00Z
Antigens
CD
Antigens
CD3
Antigens
Differentiation
Down-Regulation
Humans
Interleukin-2
Jurkat Cells
Lymphocyte Activation
Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
Membrane Proteins
Mitogen-Activated Protein Kinases
Protein Phosphatase 2
Protein Tyrosine Phosphatases
Receptors
Antigen
T-Cell
Receptors
Interleukin-2
Signal Transduction
T-Lymphocytes
Journal of Leukocyte Biology
Journal of Leukocyte Biology
74
6
1102
1107
10.1189/jlb.0503198
Immunology and Infectious Disease
Cytotoxic T-lymphocyte-associated antigen (CTLA)-4 is an activation-induced receptor that down-regulates T cell responses by antagonizing B7-dependent costimulation and/or by transducing a negative signal. The mechanism of CTLA-4-mediated negative signaling is unknown. Recently, it has been postulated that CTLA-4 inhibits T cell activation by causing specific dephosphorylation of the T cell receptor (TCR)-zeta chain of the antigen-receptor complex through an lck-dependent recruitment of the Src homology-2-containing tyrosine phosphatase-2. To test this hypothesis, we generated stably transfected T cell clones expressing doxycycline-inducible CTLA-4 with CD25:TCR-zeta (CD25-zeta) or CD25:CD3-epsilon (CD25-epsilon) fusion proteins. In these clones, ligation of CD25-zeta or of CD25-epsilon with antibodies against CD25 induced full T cell activation, as illustrated by extracellular signal-regulated kinase (ERK) activation and interleukin (IL)-2 production. More importantly, coligation of CTLA-4 with CD25-zeta or of CTLA-4 with CD25-epsilon in the respectively transfected clones inhibited ERK activation and IL-2 production, demonstrating that CTLA-4 does not specifically inhibit signals from TCR-zeta but can also inhibit signals from CD3-epsilon. Our results suggest that the target specificity of CTLA-4 is determined by its coligation with any given transmembrane receptor rather than by its intracellular mediators.
https://ir.lib.uwo.ca/immunologypub/30
oai:ir.lib.uwo.ca:immunologypub-1033
2009-11-29T11:01:03Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:biochempub
publication:mni
publication:robarts
publication:biochem
publication:institutes
14585965
Regulation of T-cell Activation by Phosphodiesterase 4B2 Requires its Dynamic Redistribution during Immunological Synapse Formation
Arp, Jacqueline
Kirchhof, Mark G.
Baroja, Miren L.
Nazarian, Steven H.
Chau, Thu A.
Strathdee, Craig A.
Ball, Eric H.
Madrenas, Joaquín
Article
2003-11-01T08:00:00Z
3'
5'-Cyclic-AMP Phosphodiesterases
Cell Compartmentation
Cyclic Nucleotide Phosphodiesterases
Type 4
Enzyme Activation
Humans
Interleukin-2
Jurkat Cells
Lymphocyte Activation
Membrane Microdomains
Protein Structure
Tertiary
Receptors
Antigen
T-Cell
Recombinant Fusion Proteins
Sequence Deletion
Signal Transduction
T-Lymphocytes
Molecular and Cellular Biology
Molecular and Cellular Biology
23
22
8042
8057
10.1128/MCB.23.22.8042-8057.2003
Immunology and Infectious Disease
Medical Biochemistry
Stimulation of T cells through their antigen receptors (TCRs) causes a transient increase in the intracellular concentration of cyclic AMP (cAMP). However, sustained high levels of cAMP inhibit T-cell responses, suggesting that TCR signaling is coordinated with the activation of cyclic nucleotide phosphodiesterases (PDEs). The molecular basis of such a pathway is unknown. Here we show that TCR-dependent signaling activates PDE4B2 and that this enhances interleukin-2 production. Such an effect requires the regulatory N terminus of PDE4B2 and correlates with partitioning within lipid rafts, early targeting of this PDE to the immunological synapse, and subsequent accumulation in the antipodal pole of the T cell as activation proceeds.
https://ir.lib.uwo.ca/immunologypub/31
oai:ir.lib.uwo.ca:immunologypub-1034
2009-11-29T11:07:15Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
12660223
Peritoneal Dialysis Solutions Inhibit the Differentiation and Maturation of Human Monocyte-derived Dendritic Cells: Effect of Lactate and Glucose-degradation Products
Puig-Kröger, Amaya
Pello, Oscar Muñiz
Selgas, Rafael
Criado, Gabriel
Bajo, M-Auxiliadora
Sánchez-Tomero, Jose A.
Alvarez, Vicente
del Peso, Gloria
Sánchez-Mateos, Paloma
Holmes, Clifford
Faict, Dirk
López-Cabrera, Manuel
Madrenas, Joaquín
Corbí, Angel L.
Article
2003-04-01T08:00:00Z
Antigens
CD1
Blotting
Western
Cell Adhesion Molecules
Cell Differentiation
Cell Division
DNA
Dendritic Cells
Dialysis Solutions
Electrophoretic Mobility Shift Assay
Flow Cytometry
Glycosylation End Products
Advanced
Humans
Interleukin-12
Interleukin-6
Lectins
C-Type
Lipopolysaccharides
Monocytes
NF-kappa B
Peritoneal Dialysis
Receptors
Cell Surface
Sodium Lactate
Tumor Necrosis Factor-alpha
Journal of Leukocyte Biology
Journal of Leukocyte Biology
73
4
482
492
10.1189/jlb.0902451
Immunology and Infectious Disease
Peritoneal dialysis (PD) is a well-established therapy for end-stage renal failure, but its efficiency is limited by recurrent peritonitis. As PD solutions impair local inflammatory responses within the peritoneal cavity, we have analyzed their influence on the in vitro maturation of human monocyte-derived dendritic cells (MDDC). Evaluation of MDDC maturation parameters [expression of adhesion and costimulatory molecules, receptor-mediated endocytosis, allogeneic T cell activation, production of tumor necrosis factor alpha, interleukin (IL)-6 and IL-12 p70, and nuclear factor (NF)-kappaB activation] revealed that currently used PD solutions differentially inhibit the lipopolysaccharide (LPS)-induced maturation of MDDC, an inhibition that correlated with their ability to impair the LPS-stimulated NF-kappaB activation. Evaluation of PD components revealed that sodium lactate and glucose-degradation products impaired the acquisition of maturation parameters and NF-kappaB activation in a dose-dependent manner. Moreover, PD solutions impaired monocyte-MDDC differentiation, inhibiting the acquisition of DC markers such as CD1a and DC-specific intercellular adhesion molecule-3 grabbing nonintegrin (CD209). These findings have important implications for the initiation of immune responses under high lactate conditions, such as those occurring within tumor tissues or after macrophage activation.
https://ir.lib.uwo.ca/immunologypub/32
oai:ir.lib.uwo.ca:vascularpub-1014
2009-12-21T02:09:01Z
publication:vascularpub
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:biochempub
publication:mni
publication:robarts
publication:biochem
publication:institutes
12551893
Genomic Organization and Evolution of the CX3CR1/CCR8 Chemokine Receptor Locus
DeVries, Mark E.
Cao, Henian
Wang, Jian
Xu, Luoling
Kelvin, Alyson A.
Ran, Longsi
Chau, Luan A.
Madrenas, Joaquin
Hegele, Robert A.
Kelvin, David J.
Article
2003-04-04T08:00:00Z
Animals
Base Sequence
Chromosomes
Human
Pair 3
Conserved Sequence
Evolution
Molecular
Gene Duplication
Genome
Humans
Membrane Proteins
Mice
Molecular Sequence Data
Multigene Family
Phylogeny
Polymorphism
Single Nucleotide
Promoter Regions
Genetic
Receptors
CCR5
Receptors
CCR8
Receptors
Chemokine
Takifugu
Journal of Biological Chemistry
278
14
11985
11994
10.1074/jbc.M211422200
Biochemistry
Medical Immunology
Medical Microbiology
The chemokine receptors CCR8 and CX3CR1 are key players in adaptive immunity and are co-receptors for human immunodeficiency virus. We describe here the genomic organization and evolutionary history of both of these genes. CX3CR1 has three promoters that transcribe three separate exons that are spliced with a fourth exon containing the coding region. CCR8 has two promoters. One promoter produces a transcript of two spliced exons, and the other promoter transcribes an exon containing the coding region and lacks introns. We analyzed these promoters in the context of a luciferase reporter and identified several positive and negative regulatory elements. Identification of the genomic organization of these genes in mouse demonstrates a similar organization for CCR8, but mouse CX3CR1 lacks two of the human promoters and has an additional mouse-specific promoter that transcribes only the exon containing the coding region and therefore resembles the organization of the human and mouse CCR8 genes. We also identify two nontranscribed regions that are highly conserved between human and mouse CX3CR1 containing possible regulatory elements. Examination of the CX3CR1 and CCR8 genes and surrounding genomic regions indicates that these genes are the result of the duplication of an ancestral gene prior to the divergence of teleost fish. We characterize single nucleotide polymorphisms in the promoters of human CCR8 and CX3CR1 and establish linkage relationships between CX3CR1 promoter polymorphisms and two previously described CX3CR1 coding polymorphisms associated with human immunodeficiency virus disease progression and arteriosclerosis susceptibility.
https://ir.lib.uwo.ca/vascularpub/25
oai:ir.lib.uwo.ca:immunologypub-1036
2009-11-29T11:17:31Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
12705849
A SLAT in the Th2 Signalosome
Madrenas, Joaquín
Article
2003-04-01T08:00:00Z
Animals
Cell Differentiation
Cell Lineage
DNA-Binding Proteins
Humans
Nuclear Proteins
Receptors
Antigen
T-Cell
Signal Transduction
Th1 Cells
Th2 Cells
Immunity
Immunity
18
4
459
461
10.1016/S1074-7613(03)00089-X
Immunology and Infectious Disease
There is abundant information on the distinguishing features of TCR-mediated signaling in Th1 and Th2 cells. However, the primary signals that determine the commitment and differentiation of naive T cells toward those T helper subsets, especially prior to the contribution of polarizing cytokines, remain elusive. This minireview discusses the potential contribution of SLAT in favoring differentiation along the Th2 lineage and how this may bring us closer to a framework model for Th1/Th2 differentiation.
https://ir.lib.uwo.ca/immunologypub/34
oai:ir.lib.uwo.ca:immunologypub-1039
2009-11-29T11:31:43Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
11994459
Inhibition of CTLA-4 Function by the Regulatory Subunit of Serine/Threonine Phosphatase 2A
Baroja, Miren L.
Vijayakrishnan, Lalitha
Bettelli, Estelle
Darlington, Peter J.
Chau, Thu A.
Ling, Vincent
Collins, Mary
Carreno, Beatriz M.
Madrenas, Joaquín
Kuchroo, Vijay K.
Article
2002-05-15T07:00:00Z
Amino Acid Motifs
Animals
Antigens
CD
Antigens
Differentiation
Cell Line
Transformed
Cytoplasm
Down-Regulation
Humans
Immunoconjugates
Immunosuppressive Agents
Jurkat Cells
Ligands
Lymphocyte Activation
Lysine
Mice
Mutagenesis
Site-Directed
Phosphoprotein Phosphatases
Phosphorylation
Protein Binding
Protein Phosphatase 2
Protein Structure
Tertiary
Receptors
Antigen
T-Cell
T-Lymphocytes
Journal of Immunology
Journal of Immunology
168
10
5070
5078
Immunology and Infectious Disease
The catalytic subunit of the serine/threonine phosphatase 2A (PP2A) can interact with the cytoplasmic tail of CTLA-4. However, the molecular basis and the biological significance of this interaction are unknown. In this study, we report that the regulatory subunit of PP2A (PP2AA) also interacts with the cytoplasmic tail of CTLA-4. Interestingly, TCR ligation induces tyrosine phosphorylation of PP2AA and its dissociation from CTLA-4 when coligated. The association between PP2AA and CTLA-4 involves a conserved three-lysine motif in the juxtamembrane portion of the cytoplasmic tail of CTLA-4. Mutations of these lysine residues prevent the binding of PP2AA and enhance the inhibition of IL-2 gene transcription by CTLA-4, indicating that PP2A represses CTLA-4 function. Our data imply that the lysine-rich motif in CTLA-4 may be used to identify small molecules that block its binding to PP2A and act as agonists for CTLA-4 function.
https://ir.lib.uwo.ca/immunologypub/37
oai:ir.lib.uwo.ca:immunologypub-1035
2009-11-29T11:13:05Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
12859525
Viewpoint: Therapeutic Implications of CTLA-4 Compartmentalization
Baroja, Miren L.
Madrenas, Joaquín
Article
2003-08-01T07:00:00Z
Antigens
CD
Antigens
Differentiation
Cell Compartmentation
Humans
Signal Transduction
T-Lymphocytes
American Journal of Transplantation
American Journal of Transplantation
3
8
919
926
10.1034/j.1600-6143.2003.00182.x
Immunology and Infectious Disease
Understanding the regulatory events involved in the activation and inactivation of T cells is crucial to develop therapeutic approaches for autoimmune diseases and for organ transplantation. Co-stimulatory signals delivered through the CD28 receptor and inhibitory signals through CTLA-4 are required for the proper modulation of T cell responses and the induction and maintenance of peripheral tolerance. Manipulation of these signals is emerging as a potential strategy to prevent allograft rejection in different animal models. Recent data on the compartmentalization and the structural features of CTLA-4 within T cells provides critical information not only on the molecular basis of T cell inactivation by CTLA-4, but also on the key requirements for the successful development of therapeutic strategies targeting this molecule.
https://ir.lib.uwo.ca/immunologypub/33
oai:ir.lib.uwo.ca:immunologypub-1037
2009-11-29T11:22:06Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
12067763
Clustering of a Lipid-raft Associated Pool of ERM Proteins at the Immunological Synapse upon T cell Receptor or CD28 Ligation
Tomas, Elizabeth M.
Chau, Thu A.
Madrenas, Joaquín
Article
2002-09-02T07:00:00Z
Antigens
CD28
Cytoskeletal Proteins
DNA-Binding Proteins
Humans
Jurkat Cells
Membrane Microdomains
Microscopy
Confocal
Phosphoproteins
Phosphorylation
Receptors
Antigen
T-Cell
Transcription Factors
Immunology Letters
Immunology Letters
83
2
143
147
10.1016/S0165-2478(02)00075-5
Immunology and Infectious Disease
Although ezrin is tyrosine phosphorylated following TCR ligation, its biological role in T cell activation is not known. Here, we shhow that ezrin clusters at the immunological synapse upon T cell stimulation. Clustering of ezrin can be triggered by TCR ligation, or, more efficiently, by CD28 ligation. The clusters of ezrin at the immunological synapse include serine/threonine phosphorylated ezrin predominantly located within cell membrane lipid rafts. Based on these data, we propose that ezrin may play a role in the formation/stabilization of lipid raft signalosomes at the immunological synapse and therefore contribute to sustain TCR-dependent signalling.
https://ir.lib.uwo.ca/immunologypub/35
oai:ir.lib.uwo.ca:immunologypub-1038
2009-11-29T11:26:15Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
12021313
Surface Cytotoxic T Lymphocyte-associated Antigen 4 Partitions within Lipid Rafts and Relocates to the Immunological Synapse under Conditions of Inhibition of T cell Activation.
Darlington, Peter J.
Baroja, Miren L.
Chau, Thu A.
Siu, Eric
Ling, Vincent
Carreno, Beatriz M.
Madrenas, Joaquín
Article
2002-05-20T07:00:00Z
Antigen-Presenting Cells
Antigens
CD
Antigens
Differentiation
Flow Cytometry
Glycosylphosphatidylinositols
Humans
Immunoconjugates
Interleukin-2
Jurkat Cells
Lymphocyte Activation
Membrane Microdomains
Microscopy
Confocal
Molecular Sequence Data
Protein Transport
Receptors
Antigen
T-Cell
Signal Transduction
T-Lymphocytes
Journal of Experimental Medicine
Journal of Experimental Medicine
195
10
1337
1347
10.1084/jem.20011868
Immunology and Infectious Disease
T cell activation through the T cell receptor (TCR) involves partitioning of receptors into discrete membrane compartments known as lipid rafts, and the formation of an immunological synapse (IS) between the T cell and antigen-presenting cell (APC). Compartmentalization of negative regulators of T cell activation such as cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is unknown. Recent crystal structures of B7-ligated CTLA-4 suggest that it may form lattices within the IS which could explain the mechanism of action of this molecule. Here, we show that after T cell stimulation, CTLA-4 coclusters with the TCR and the lipid raft ganglioside GM1 within the IS. Using subcellular fractionation, we show that most lipid raft-associated CTLA-4 is on the T cell surface. Such compartmentalization is dependent on the cytoplasmic tail of CTLA-4 and can be forced with a glycosylphosphatidylinositol-anchor in CTLA-4. The level of CTLA-4 within lipid rafts increases under conditions of APC-dependent TCR-CTLA-4 coligation and T cell inactivation. However, raft localization, although necessary for inhibition of T cell activation, is not sufficient for CTLA-4-mediated negative signaling. These data demonstrate that CTLA-4 within lipid rafts migrates to the IS where it can potentially form lattice structures and inhibit T cell activation.
https://ir.lib.uwo.ca/immunologypub/36
oai:ir.lib.uwo.ca:immunologypub-1040
2009-11-29T12:04:51Z
publication:mnipub
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
Oral Administration of the Probiotic Combination Lactobacillus Rhamnosus GR-1 and L. Fermentum RC-14 for Human Intestinal Applications
Gardiner, Gillian E.
Heinemann, Christine
Baroja, Miren L.
Bruce, Andrew W.
Beuerman, Dee
Madrenas, Joaquín
Reid, Gregor
Article
2002-01-01T08:00:00Z
Probiotic
Lactobacilli
Gastrointestinal tract
International Dairy Journal
International Dairy Journal
12
2011-02-03
191
196
10.1016/S0958-6946(01)00138-8
Immunology and Infectious Disease
Lactobacillus rhamnosus GR-1 and L. fermentum RC-14, previously characterized as urogenital probiotics were evaluated for human intestinal applications. RC-14 and GR-1 were tolerant to 0.3 and 0.5% (w/v) bile, respectively. Both strains were suspended in skim milk, stored as a frozen concentrate and administered in combination to five healthy women twice daily for 14 days. Faecal samples were analyzed and the Lactobacillus flora assessed by Randomly Amplified Polymorphic DNA (RAPD). Both strains were recovered from all subjects during the 14-day administration period and GR-1 was detected for at least 7 days post-administration in some individuals. No notable increases in serum IgG, IgA or IgM were observed and IL-2 and IL-4 were undetectable. Although IL-6 and IFN-γ levels increased slightly in some individuals, concentrations remained within normal ranges. Thus, L. rhamnosus GR-1 and L. fermentum RC-14 are bile tolerant and survive gastrointestinal transit without induction of systemic immune or inflammatory responses. These data together with the previously demonstrated probiotic properties of GR-1 and RC-14 make this strain combination potentially useful for human intestinal applications.
https://ir.lib.uwo.ca/immunologypub/38
oai:ir.lib.uwo.ca:immunologypub-1041
2009-11-29T12:19:27Z
publication:mnipub
publication:patholpub
publication:surgerypub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:pathol
publication:med
publication:mni
publication:robarts
publication:surgery
publication:institutes
11882031
Thymic Re-entry of Mature Activated T cells and Increased Negative Selection in Vascularized Allograft Recipients
Chau, L. A.
Rohekar, S.
Wang, J.-J.
Lian, D.
Chakrabarti, S.
Zhang, L.
Zhong, R.
Madrenas, J.
Article
2002-01-01T08:00:00Z
Animals
Antigen Presentation
Cell Death
Cell Movement
Heart Transplantation
Lymphocyte Activation
Male
Mice
Mice
Inbred BALB C
Mice
Inbred C57BL
Neovascularization
Physiologic
T-Lymphocytes
Thymus Gland
Transplantation Immunology
Transplantation
Homologous
Clinical and Experimental Immunology
Clinical and Experimental Immunology
127
1
43
52
10.1046/j.1365-2249.2002.01717.x
Immunology and Infectious Disease
Pathology
Surgery
Transplantation tolerance is a dynamic state that involves several homeostatic mechanisms intrinsic to the host. One of these mechanisms is activation-induced T cell death (AICD). However, it is unclear where AICD takes place during alloreactive responses. Since activated T cells can re-enter the thymus, we hypothesized that mature T cells activated by an allograft could be deleted upon re-entry into the thymus. To test this hypothesis, we used wild-type or 2C TCR transgenic mice receiving syngeneic or allogeneic heterotopic, vascularized heart grafts. First, we demonstrated that ex vivo CFSE-labelled T cells re-entered the thymus when transferred into allograft recipients but not when transferred into isograft recipients. Next, we compared the changes in cell subset numbers and incidence of apoptosis in the thymi and spleens of allograft or isograft recipients. Seven days after transplantation, at a time in which all the allografts were undergoing rejection, cells expressing donor-MHC class II molecules had migrated to the thymus and to the spleen. In the thymus of allograft recipients, overall cellularity was significantly reduced by 40% and associated with an increase in the number of double negative (CD4-CD8-) thymocytes and a decrease in double positive (CD4+CD8+) thymocytes, consistent with increased negative selection of thymocytes. Additionally, thymi of allograft recipients showed an increase in the number of recently activated, mature T cells (TCRhi, CD25+, CD44+) and a significant increase in the number of apoptotic cells, especially in the thymic medulla, that involved mature T cells as indicated by the TCRhi, CD44+, CD4 or CD8 single positive phenotype. Spleens of allograft recipients were increased in size and cellularity but did not show any of the changes in cell subsets seen in the thymi. Our data show that after allografting there is an increase in apoptotic cell death that is associated with negative selection of developing thymocytes as well as of alloreactive mature T cells that have re-entered the thymus upon activation in the periphery. This may occur upon migration of graft-derived antigen-presenting cells to the thymus.
https://ir.lib.uwo.ca/immunologypub/39
oai:ir.lib.uwo.ca:immunologypub-1044
2009-11-29T12:23:36Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
11266941
Generation of Partial Agonist Ligands of the T-cell Receptor by Engineering of Antibodies against CD3
Chau, L. A.
Tso, J. Y.
Madrenas, J.
Article
2001-02-01T08:00:00Z
Antibodies
Antigens
CD3
Cyclin-Dependent Kinase Inhibitor p21
Cyclins
Humans
Leukocytes
Mononuclear
Ligands
Muromonab-CD3
Phosphorylation
Protein-Tyrosine Kinases
Receptors
Antigen
T-Cell
ZAP-70 Protein-Tyrosine Kinase
Transplantation Proceedings
Transplantation Proceedings
33
1-2
528
529
10.1016/S0041-1345(00)02125-4
Immunology and Infectious Disease
https://ir.lib.uwo.ca/immunologypub/41
oai:ir.lib.uwo.ca:immunologypub-1045
2009-11-29T12:27:29Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
11266781
The Role of Ezrin in T-cell Receptor-dependent Signaling
Tomas, E. M.
Darlington, P. J.
Chau, L. A.
Madrenas, J.
Article
2001-02-01T08:00:00Z
Animals
Cell Line
Cytoskeletal Proteins
Cytoskeleton
Humans
Jurkat Cells
Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
Mice
Phosphoproteins
Phosphorylation
Protein-Tyrosine Kinases
Receptors
Antigen
T-Cell
ZAP-70 Protein-Tyrosine Kinase
Transplantation Proceedings
Transplantation Proceedings
33
1-2
207
208
10.1016/S0041-1345(00)01976-X
Immunology and Infectious Disease
https://ir.lib.uwo.ca/immunologypub/42
oai:ir.lib.uwo.ca:physpharmpub-1023
2010-01-07T07:29:39Z
publication:mnipub
publication:physpharmpub
publication:paed
publication:pmid
publication:immunologypub
publication:faculties
publication:physpharm
publication:mni
publication:robarts
publication:institutes
publication:paedpub
11481253
Inhibition of Cytokine Production and Interference in IL-2 Receptor-mediated Jak-Stat Signaling by the Hydroxylamine Metabolite of Sulfamethoxazole
Hess, David A.
O'Leary, Erin F.
Lee, James T.
Almawi, Wassim Y.
Madrenas, Joaquin
Rieder, Michael J.
Article
2001-08-01T07:00:00Z
Cytokines
DNA-Binding Proteins
Humans
Interferon-gamma
Interleukin-1
Interleukin-4
Janus Kinase 1
Janus Kinase 3
Milk Proteins
Phosphorylation
Protein-Tyrosine Kinases
Receptors
Interleukin-2
STAT3 Transcription Factor
STAT5 Transcription Factor
Signal Transduction
Sulfamethoxazole
Trans-Activators
Tumor Necrosis Factor-alpha
FASEB Journal
FASEB Journal
15
10
1855
1857
10.1096/fj.00-0583fje
Medical Immunology
Medical Microbiology
Pediatrics
Pharmacy and Pharmaceutical Sciences
Sulfonamides, used for the treatment of opportunistic infections in immunocompromised patients, are associated with a high incidence of adverse drug events, including severe hypersensitivity reactions. Imbalances in the production and detoxification of reactive sulfonamide metabolites have been implicated in the pathogenesis of these life-threatening reactions. The hydroxylamine metabolite of sulfamethoxazole (SMX-HA) inhibits the proliferation of mitogen-stimulated peripheral blood mononuclear cells (PBMCs) in vitro without reducing Interleukin 2 (IL-2) expression. We investigated the effects of SMX-HA on accessory cytokine expression and IL-2 receptor (IL-2R) mediated signal transduction. SMX-HA did not reduce significantly mRNA production of proinflammatory [tumor necrosis factor a (TNF-a) and IL-1b], Th1-type (IFN-g), and Th2-type cytokines (IL-4 and IL-10). Sublethal concentrations of SMX-HA (25 mM) reduced significantly the production of TNF-a, IL-1b, and IL4 protein without inhibiting the production of IFN-g. This finding suggests that exposure to SMX-HA might direct a response towards a Th-1 vs. a Th-2 response. Immunoblot analysis of IL-2R-mediated Janus kinases and signal transduction activators of transcription (Jak-Stat) signal transduction revealed diminished phosphorylation of Jak1 and Jak3 and inhibited downstream phosphorylation of Stat3, Stat5a, and IL-2Rg in phytohemagglutinin/rIL-2 activated PBMCs treated with SMX-HA. SMX-HA did not inhibit Jak association with IL-2Rg or IL-2Rb. These data illustrated that sublethal concentrations of SMX-HA interfere with IL-2R-mediated signal transduction, resulting in altered cytokine production and inhibition of lymphocyte proliferation.
https://ir.lib.uwo.ca/physpharmpub/28
oai:ir.lib.uwo.ca:immunologypub-1042
2009-11-29T12:15:16Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
11585897
Zap-70-independent Ca(2+) Mobilization and Erk Activation in Jurkat T cells in Response to T-cell Antigen Receptor Ligation
Shan, X.
Balakir, R.
Criado, G.
Wood, J. S.
Seminario, M. C.
Madrenas, J.
Wange, R. L.
Article
2001-11-01T08:00:00Z
Antigens
CD3
Calcium
Cell Line
Cross-Linking Reagents
DNA-Binding Proteins
Dose-Response Relationship
Drug
Enzyme Activation
Enzyme Inhibitors
Flow Cytometry
Genes
Reporter
Humans
Isoenzymes
Jurkat Cells
Kinetics
MAP Kinase Kinase 1
Mitogen-Activated Protein Kinase Kinases
Mitogen-Activated Protein Kinases
Models
Biological
NFATC Transcription Factors
Nuclear Proteins
Phospholipase C gamma
Phosphorylation
Precipitin Tests
Protein Binding
Protein Kinase C
Protein-Serine-Threonine Kinases
Protein-Tyrosine Kinases
Proto-Oncogene Proteins c-raf
Time Factors
Transcription Factors
Type C Phospholipases
Up-Regulation
ZAP-70 Protein-Tyrosine Kinase
Molecular and Cellular Biology
Molecular and Cellular Biology
21
21
7137
7149
10.1128/MCB.21.21.7137-7149.2001
Immunology and Infectious Disease
The tyrosine kinase ZAP-70 has been implicated as a critical intermediary between T-cell antigen receptor (TCR) stimulation and Erk activation on the basis of the ability of dominant negative ZAP-70 to inhibit TCR-stimulated Erk activation, and the reported inability of anti-CD3 antibodies to activate Erk in ZAP-70-negative Jurkat cells. However, Erk is activated in T cells receiving a partial agonist signal, despite failing to activate ZAP-70. This discrepancy led us to reanalyze the ZAP-70-negative Jurkat T-cell line P116 for its ability to support Erk activation in response to TCR/CD3 stimulation. Erk was activated by CD3 cross-linking in P116 cells. However, this response required a higher concentration of anti-CD3 antibody and was delayed and transient compared to that in Jurkat T cells. Activation of Raf-1 and MEK-1 was coincident with Erk activation. Remarkably, the time course of Ras activation was comparable in the two cell lines, despite proceeding in the absence of LAT tyrosine phosphorylation in the P116 cells. CD3 stimulation of P116 cells also induced tyrosine phosphorylation of phospholipase C-gamma1 (PLCgamma1) and increased the intracellular Ca(2+) concentration. Protein kinase C (PKC) inhibitors blocked CD3-stimulated Erk activation in P116 cells, while parental Jurkat cells were refractory to PKC inhibition. The physiologic relevance of these signaling events is further supported by the finding of PLCgamma1 tyrosine phosphorylation, Erk activation, and CD69 upregulation in P116 cells on stimulation with superantigen and antigen-presenting cells. These results demonstrate the existence of two pathways leading to TCR-stimulated Erk activation in Jurkat T cells: a ZAP-70-independent pathway requiring PKC and a ZAP-70-dependent pathway that is PKC independent.
https://ir.lib.uwo.ca/immunologypub/40
oai:ir.lib.uwo.ca:mnipub-1014
2010-01-24T07:47:16Z
publication:mnipub
publication:surgerypub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:surgery
publication:institutes
10540214
CD40-deficient Dendritic Cells Producing Interleukin-10, but not Interleukin-12, Induce T-cell Hyporesponsiveness In Vitro and Prevent Acute Allograft Rejection
Gao, J. X.
Madrenas, J.
Zeng, W.
Cameron, M. J.
Zhang, Z.
Wang, J. J.
Zhong, R.
Grant, D.
Article
1999-10-01T07:00:00Z
Adoptive Transfer
Animals
Antigens
CD40
Cells
Cultured
Dendritic Cells
Flow Cytometry
Graft Rejection
Immune Tolerance
Interleukin-10
Interleukin-12
Lipopolysaccharides
Male
Mice
Mice
Inbred BALB C
Mice
Inbred C3H
Mice
Inbred C57BL
T-Lymphocytes
Transplantation
Homologous
Immunology
Immunology
98
2
159
170
10.1046/j.1365-2567.1999.00863.x
Immunology and Infectious Disease
Microbiology
The induction of an immune response or tolerance is mediated by corresponding subsets of dendritic cells (DC). However, the property of tolerogenic DC is not clear. Recently, we have characterized a population of CD11c+ splenic DC derived from long-term mixed leucocyte culture (LT-MLC), which are able to proliferate upon stimulation and have a strong primary mixed leucocyte reaction (MLR)-stimulating activity in conventional MLR. In this study, we show that, in contrast to the irradiated ones, non-irradiated LT-MLC-derived DC induce polyclonal antigen-specific T-cell hyporesponsiveness when cocultured with allogeneic splenocytes for 3-11 days. The degree of the hyporesponsiveness increased with the length of coculture. Although these DC expressed major histocompatibility complex class II and B7 costimulatory molecules, which are down-regulated during coculture, they expressed very low or undetectable CD40 before and after coculture, respectively. The CD40-deficient DC spontaneously produce interleukin-10 (IL-10), but not IL-12. The skewed balance between IL-10 and IL-12 is associated with their capability to induce T-cell hyporesponsiveness, because a neutralizing antibody to IL-10, exogenous recombinant IL-12 or lipopolysaccharide (LPS) significantly blocked the hyporesponsiveness. Accordingly, infusion of a small number of non-irradiated LT-MLC-derived DC (5x105) significantly prolonged the survival of a vascularized heterotopic murine heart transplant, whereas irradiated DC accelerated graft rejection. These data suggest that CD40-deficient DC producing IL-10, but not IL-12 can induce T-cell hyporesponsiveness in vitro and in vivo.
https://ir.lib.uwo.ca/mnipub/17
oai:ir.lib.uwo.ca:immunologypub-1046
2009-11-29T12:31:16Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
10903737
CTLA-4 (CD152) Can Inhibit T cell Activation by Two Different Mechanisms Depending on Its Level of Cell Surface Expression
Carreno, Beatriz M.
Bennett, Frann
Chau, Thu A.
Ling, Vincent
Luxenberg, Deborah
Jussif, Jason
Baroja, Miren L.
Madrenas, Joaquin
Article
2000-08-01T07:00:00Z
Amino Acid Sequence
Antibodies
Monoclonal
Antigens
CD
Antigens
CD28
Antigens
CD3
Antigens
CD80
Antigens
CD86
Antigens
Differentiation
Cell Membrane
Cytoplasm
Down-Regulation
Doxycycline
Humans
Immunoconjugates
Immunoglobulin Fc Fragments
Immunosuppressive Agents
Interleukin-2
Jurkat Cells
Lymphocyte Activation
Membrane Glycoproteins
Microspheres
Molecular Sequence Data
Peptide Fragments
Recombinant Fusion Proteins
Signal Transduction
T-Lymphocytes
Journal of Immunology
Journal of Immunology
165
3
1352
1356
Immunology and Infectious Disease
CTLA-4 (CD152) engagement results in down-regulation of T cell activation. Two mechanisms have been postulated to explain CTLA-4 inhibition of T cell activation: negative signaling and competitive antagonism of CD28:B7-mediated costimulation. We assessed the contributions of these two mechanisms using a panel of T cell lines expressing human CTLA-4 with mutations in the cytoplasmic region. Under conditions of B7-independent costimulation, inhibition of IL-2 production following CTLA-4 engagement required the CTLA-4 cytoplasmic region. In contrast, under B7-dependent costimulation, inhibition of IL-2 production by CTLA-4 engagement was directly proportional to CTLA-4 cell surface levels and did not require its cytoplasmic region. Thus, CTLA-4 down-regulates T cell activation by two different mechanisms-delivery of a negative signal or B7 sequestration-that are operational depending on the levels of CTLA-4 surface expression. These two mechanisms may have distinct functional outcomes: rapid inhibition of T cell activation or induction of T cell anergy.
https://ir.lib.uwo.ca/immunologypub/43
oai:ir.lib.uwo.ca:immunologypub-1047
2009-11-29T12:35:41Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
10958178
Prevention of Diabetes Mellitus in the Non-obese Diabetic Mouse Strain with Monoclonal Antibodies against the CD45RB Molecule
Abu-Hadid, M. M.
Lazarovits, A. I.
Madrenas, J.
Article
2000-07-01T07:00:00Z
Animals
Antibodies
Monoclonal
Antigens
CD45
Autoimmunity
Diabetes Mellitus
Female
Insulin
Mice
Mice
Inbred NOD
Pancrelipase
Autoimmunity
Autoimmunity
32
1
73
76
10.3109/08916930008995990
Immunology and Infectious Disease
https://ir.lib.uwo.ca/immunologypub/44
oai:ir.lib.uwo.ca:immunologypub-1051
2009-12-12T01:48:00Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:mni
publication:robarts
publication:institutes
10075104
Differential Signalling by Variant Ligands of the T Cell Receptor and the Kinetic Model of T Cell Activation
Madrenas, Joaquín
Article
1999-01-22T08:00:00Z
Humans
Kinetics
Ligands
Lymphocyte Activation
Models
Immunological
Receptors
Antigen
T-Cell
Signal Transduction
T-Lymphocytes
Life Sciences
Life Sciences
64
9
717
731
10.1016/S0024-3205(98)00381-6
Immunology and Infectious Disease
The structural basis of T cell activation through the T cell receptor is still a major unresolved issue in T cell biology. The wealth of information on the generation and structure of T cell receptor ligands and the biochemistry of signal transduction from this receptor have been useful in the initial approach to explain how T cell activation occurs. More recently, the generation of variant T cell receptor ligands with partial agonist or antagonist properties, the determination of crystal structures for unengaged and engaged T cell receptors, and the kinetics of T cell receptor interactions with peptide:MHC molecule complexes have provided new insights on T cell receptor function. The common theme arising from these experiments is that the T cell receptor is a versatile signalling machine, with an inherent flexibility for ligand recognition that translates in different signalling patterns. Here, I will review the data on differential signalling from the T cell receptor upon recognition of partial agonist and antagonist ligands and how these data impact on a more general kinetic model of T cell receptor-mediated activation.
https://ir.lib.uwo.ca/immunologypub/47
oai:ir.lib.uwo.ca:immunologypub-1052
2009-12-12T01:55:53Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:mni
publication:robarts
publication:institutes
10438919
Phospho-LAT-independent Activation of the Ras-mitogen-activated Protein Kinase Pathway: A Differential Recruitment Model of TCR Partial Agonist Signaling
Chau, Luan A.
Madrenas, Joaquín
Article
1999-08-15T07:00:00Z
Adaptor Proteins
Signal Transducing
Animals
Calcium-Calmodulin-Dependent Protein Kinases
Carrier Proteins
Clone Cells
Enzyme Activation
GRB2 Adaptor Protein
Lymphocyte Activation
Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
Membrane Proteins
Mice
Models
Biological
Oligopeptides
Peptide Fragments
Phosphoproteins
Phosphorylation
Protein-Tyrosine Kinases
Proteins
Receptors
Antigen
T-Cell
Signal Transduction
T-Lymphocytes
ZAP-70 Protein-Tyrosine Kinase
ras Proteins
Journal of Immunology
Journal of Immunology
163
4
1853
1858
Immunology and Infectious Disease
Stimulation of mature T cells with agonist ligands of the Ag receptor (TCR) causes rapid phosphorylation of tyrosine-based activation motifs in the intracellular portion of TCR-zeta and CD3 and activation of several intracellular signaling cascades. Coordinate activation of these pathways is dependent on Lck- and ZAP-70-mediated tyrosine phosphorylation of a 36-kDa linker for activation of T cells and subsequent recruitment of phospholipase C-gamma1, Grb2-SOS, and SLP-76-vav. Here, we show that TCR partial agonist ligands can selectively activate one of these pathways, the Ras-mitogen-activated protein kinase pathway, by inducing recruitment of Grb2-SOS complexes to incompletely phosphorylated p21 phospho-TCR-zeta. This bypasses the need for activation of Lck and ZAP-70, and for phosphorylation of the linker for activation of T cells to activate Ras. We propose a general model in which differential recruitment of activating complexes away from transmembrane linker proteins may determine selective activation of a given signaling pathway.
https://ir.lib.uwo.ca/immunologypub/48
oai:ir.lib.uwo.ca:physpharmpub-1024
2010-01-07T07:37:27Z
publication:mnipub
publication:physpharmpub
publication:paed
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:physpharm
publication:mni
publication:robarts
publication:institutes
publication:paedpub
10506572
Cytotoxicity of Sulfonamide Reactive Metabolites: Apoptosis and Selective Toxicity of CD8(+) Cells by the Hydroxylamine of Sulfamethoxazole
Hess, David A.
Sisson, Margaret E.
Suria, Hamza
Wijsman, John
Puvanesasingham, Ram
Madrenas, Joaquín
Rieder, Michael J.
Article
1999-10-01T07:00:00Z
Apoptosis
CD8-Positive T-Lymphocytes
DNA Fragmentation
Dose-Response Relationship
Drug
Humans
Immunomagnetic Separation
Phosphatidylserines
Sulfamethoxazole
Sulfonamides
T-Lymphocyte Subsets
FASEB Journal
FASEB Journal
13
13
1688
1698
Medical Immunology
Medical Microbiology
Pediatrics
Pharmacy and Pharmaceutical Sciences
Treatment with sulfonamide antibiotics in HIV-infected patients is associated with a high incidence (> 40%) of adverse drug events, including severe hypersensitivity reactions. Sulfonamide reactive metabolites have been implicated in the pathogenesis of these adverse reactions. Sulfamethoxazole hydroxylamine (SMX-HA) induces lymphocyte toxicity and suppression of proliferation in vitro; the mechanism(s) of these immunomodulatory effects remain unknown. We investigated the cytotoxicity of SMX-HA via apoptosis on human peripheral blood mononuclear cells and purified cell subpopulations in vitro. CD19(+), CD4(+), and CD8(+) cells were isolated from human peripheral blood by positive selection of cell surface molecules by magnetic bead separation. SMX-HA induced significant CD8(+) cell death (67 +/- 7%) at 100 microM SMX-HA, with only minimal CD4(+) cell death (8 +/- 4%). No significant subpopulation toxicity was shown when incubated with parent drug (SMX). Flow cytometry measuring phosphatidylserine externalization 24 h after treatment with 100 microM and 400 microM SMX-HA revealed 14.1 +/- 0.7% and 25. 6 +/- 4.2% annexin-positive cells, respectively, compared to 3.7 +/- 1.2% in control PBMCs treated with 400 microM SMX. Internucleosomal DNA fragmentation was observed in quiescent and stimulated PBMCs 48 h after incubation with SMX-HA. Our data show that CD8(+) cells are highly susceptible to the toxic effects of SMX-HA through enhanced cell death by apoptosis.
https://ir.lib.uwo.ca/physpharmpub/29
oai:ir.lib.uwo.ca:immunologypub-1048
2009-12-03T06:39:07Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
10604992
The Inhibitory Function of CTLA-4 Does Not Require Its Tyrosine Phosphorylation
Baroja, Miren L.
Luxenberg, Deborah
Chau, Thu
Ling, Vincent
Strathdee, Craig A.
Carreno, Beatriz M.
Madrenas, Joaquín
Article
2000-01-01T08:00:00Z
Antigens
CD
Antigens
CD3
Antigens
Differentiation
Cell Membrane
Cytoplasm
Enzyme Activation
Humans
Immunoconjugates
Immunosuppressive Agents
Interleukin-2
Jurkat Cells
Ligands
Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinases
Mutagenesis
Site-Directed
Phosphorylation
Protein-Tyrosine Kinases
T-Lymphocytes
Tyrosine
ZAP-70 Protein-Tyrosine Kinase
Journal of Immunology
Journal of Immunology
164
1
49
55
Immunology and Infectious Disease
CTLA-4 is a negative regulator of T cell responses. Sequence analysis of this molecule reveals the presence of two cytoplasmic tyrosine residues at positions 165 and 182 that are potential Src homology (SH)-2 domain binding sites. The role of phosphorylation of these residues in CTLA-4-mediated signaling is unknown. Here, we show that sole TCR ligation induces zeta-associated protein (ZAP)-70-dependent tyrosine phosphorylation of CTLA-4 that is important for cell surface retention of this molecule. However, CTLA-4 tyrosine phosphorylation is not required for down-regulation of T cell activation following CD3-CTLA-4 coengagement. Specifically, inhibition of extracellular signal-regulated kinase (ERK) activation and of IL-2 production by CTLA-4-mediated signaling occurs in T cells expressing mutant CTLA-4 molecules lacking the cytoplasmic tyrosine residues, and in lck-deficient or ZAP-70-deficient T cells. Therefore, CTLA-4 function involves interplay between two different levels of regulation: phosphotyrosine-dependent cell surface retention and phosphotyrosine-independent association with signaling molecules.
https://ir.lib.uwo.ca/immunologypub/45
oai:ir.lib.uwo.ca:immunologypub-1049
2009-12-03T06:42:14Z
publication:mnipub
publication:physpharmpub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:physpharm
publication:mni
publication:robarts
publication:institutes
10602045
Identification of a Novel Mechanism for Endotoxin-mediated Down-modulation of CC Chemokine Receptor Expression
Xu, Luoling
Khandaker, Masud H.
Barlic, Jana
Ran, Longsi
Borja, Miren L.
Madrenas, Joaquín
Rahimpour, Rahbar
Chen, Kong
Mitchell, Gordon
Tan, Christopher M.
DeVries, Mark
Feldman, Ross D.
Kelvin, David J.
Article
2000-01-01T08:00:00Z
Chemokine CCL2
Down-Regulation
Genistein
Humans
Lipopolysaccharides
Monocytes
Receptors
CCR2
Receptors
Chemokine
Receptors
Cytokine
Serine Endopeptidases
Serine Proteinase Inhibitors
Tosyllysine Chloromethyl Ketone
European Journal of Immunology
European Journal of Immunology
30
1
227
235
10.1002/1521-4141(200001)30:1<227::AID-IMMU227>3.0.CO;2-X
Immunology and Infectious Disease
In the present study, we explored the molecular mechanisms by which bacterial endotoxin (LPS) mediates the down-regulation of CCR2 receptors on human monocytes. We found that LPS induced a marked reduction in CCR2 cell surface protein levels which was blocked by pretreatment with the tyrosine kinase inhibitors genistein and herbimycin A. The effector mechanism underlying LPS-induced CCR2 down-modulation appears to involve the enzymatic activity of proteinases since Western blot analysis of LPS-stimulated monocytes revealed the degradation of a 38-kDa species corresponding to the CCR2B monomer. In RBL cells expressing the CCR2B-green fluorescent protein (GFP) fusion chemokine receptor, LPS stimulated the internalization and degradation of CCR2. The serine proteinase inhibitor N-alpha-p-tosyl-L-lysine chloromethyl ketone blocked LPS-induced down-modulation of CCR2 in monocytes and CCR2B-GFP in RBL cells. This work describes a previously uncharacterized mechanism for CC chemokine receptor down-modulation that is dependent upon tyrosine kinase activation and serine proteinase-mediated receptor degradation and may provide further insight into the mechanisms of leukocyte regulation during immunological and inflammatory responses.
https://ir.lib.uwo.ca/immunologypub/46
oai:ir.lib.uwo.ca:physpharmpub-1025
2010-01-07T07:42:37Z
publication:mnipub
publication:physpharmpub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:physpharm
publication:mni
publication:robarts
publication:institutes
10359100
CD45 Modulation of CXCR1 and CXCR2 in Human Polymorphonuclear Leukocytes
Mitchell, Gordon B.
Khandaker, Masud H.
Rahimpour, Rahbar
Xu, Luoling
Lazarovits, Andrew I.
Pickering, J. Geoffrey
Suria, Hamza
Madrenas, Joaquín
Pomerantz, David K.
Feldman, Ross D.
Kelvin, David J.
Article
1999-05-01T07:00:00Z
Antibodies
Monoclonal
Antigens
CD
Antigens
CD45
Benzoquinones
Cells
Cultured
Chemokine CCL2
Chemokine CCL4
Down-Regulation
Genistein
Humans
Interleukin-8
Lactams
Macrocyclic
Macrophage Inflammatory Proteins
Neutrophils
Phosphorylation
Protein-Tyrosine Kinases
Quinones
Receptors
Chemokine
Receptors
Interleukin
Receptors
Interleukin-8A
Receptors
Interleukin-8B
Tyrosine
European Journal of Immunology
European Journal of Immunology
29
5
1467
1476
10.1002/(SICI)1521-4141(199905)29:05<1467::AID-IMMU1467>3.0.CO
Medical Immunology
Medical Microbiology
Medical Physiology
All leukocytes express the cell surface glycoprotein CD45, which has intrinsic intracellular protein tyrosine phosphatase activity. CD45 is known to play a regulatory role in activation-induced signaling in lymphocytes; however, little is known of its role in non-lymphoid leukocytes. Therefore, we examined the potential effect of CD45 on chemokine-induced signaling in human neutrophils (polymorphonuclear cells, PMN). Treating isolated PMN for 2 h with an anti-CD45RB antibody (Bra11) down-modulated expression of the chemokine receptors CXCR1 and CXCR2 to 44 +/- 10% and 47 +/- 9% of their respective controls. The tyrosine kinase inhibitors genistein and herbimycin A significantly inhibited the Bra11-induced down-modulation of CXCR1 and CXCR2. Furthermore, Bra11-treated PMN were functionally inhibited in their capacity to exhibit IL-8-induced transient intracellular Ca2+ increases. Selected targeting of CXC receptors is indicated by the fact that N-formyl-Met-Leu-Phe (fMLP) receptor expression and function were not lost following Bra11 treatment. The effect of Bra11 on IL-8-mediated function and receptor expression was paralleled by decreased tyrosine phosphorylation of a 54- to 60-kDa protein. These findings indicate that CD45 can act to modulate PMN responses to chemokines; thus agents regulating CD45 can potentially modulate leukocyte traffic and may represent a novel therapeutic approach towards the treatment of inflammatory diseases.
https://ir.lib.uwo.ca/physpharmpub/30
oai:ir.lib.uwo.ca:mnipub-1013
2010-01-24T07:40:14Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
10622279
Cytoskeletal Disruption Induces T Cell Apoptosis by a Caspase-3 Mediated Mechanism
Suria, Hamza
Chau, Luan A.
Negrou, Ella
Kelvin, David J.
Madrenas, Joaquín
Article
1999-11-12T08:00:00Z
Animals
Annexin A5
Apoptosis
Caspase 3
Caspases
Cell Line
Cytochalasin B
Cytochalasin D
Cytochalasins
Cytoskeleton
DNA Fragmentation
Mice
Nucleic Acid Synthesis Inhibitors
T-Lymphocytes
Life Sciences
Life Sciences
65
25
2697
2707
10.1016/S0024-3205(99)00538-X
Immunology and Infectious Disease
Microbiology
T cell apoptosis can be triggered by different mechanisms that lead to distinctive features such as cell shrinkage, membrane blebbing, phosphatidylserine externalization, and internucleosomal DNA fragmentation. Prevailing models for the induction of apoptosis place the cytoskeleton as a distal target of the death effector molecules ('executioners'). However, the cytoskeleton can also play a role in the induction of apoptosis as suggested by the finding that cytoskeletal disruption can induce apoptosis. The mechanism by which this occurs is unknown. Here, we report that T cell apoptosis by cytoskeletal disruption involves a protein synthesis-independent mechanism leading to up-regulation of caspase-3 protease activity and increased accessibility of active caspase-3 to its substrate. Thus, cytoskeleton integrity may regulate the subcellular compartmentalization of death effector molecules.
https://ir.lib.uwo.ca/mnipub/16
oai:ir.lib.uwo.ca:immunologypub-1050
2010-01-25T01:25:31Z
publication:mnipub
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
Lymphocytes: Antigen-induced Gene Activation
Madrenas, Joaquin
Article
1999-11-01T08:00:00Z
Antigen Receptor
Lymphocyte Activation
Signal Transduction
Transcription Factors
Cytokines
Immunology and Infectious Disease
Published as an article in: <em>Encyclopedia of Life Sciences</em> (1999). This edition of the encyclopedia is not available online here, but it may be available in Western Libraries. Please use the Shared Library Catalogue's <a href="http://alpha.lib.uwo.ca/">Advanced Search</a> to check our collections.
https://ir.lib.uwo.ca/immunologypub/81
oai:ir.lib.uwo.ca:immunologypub-1054
2009-12-12T02:15:07Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
9973473
Specific CD3{varepsilon} Epsilon Association of a Phosphodiesterase 4B Isoform Determines Its Selective Tyrosine Phosphorylation after CD3 Ligation
Baroja, Miren L.
Cieslinski, Lenora B.
Torphy, Theodore J.
Wange, Ronald L.
Madrenas, Joaquín
Article
1999-02-15T08:00:00Z
3'
5'-Cyclic-AMP Phosphodiesterases
Antibodies
Monoclonal
Antigens
CD3
Blotting
Western
Cyclic Nucleotide Phosphodiesterases
Type 4
Humans
Interphase
Isoenzymes
Leukocytes
Mononuclear
Lymphocyte Activation
Phosphorylation
Precipitin Tests
Receptor-CD3 Complex
Antigen
T-Cell
Receptors
Antigen
T-Cell
T-Lymphocytes
Tyrosine
Journal of Immunology
Journal of Immunology
162
4
2016
2023
Immunology and Infectious Disease
cAMP-specific phosphodiesterases (PDE) comprise an extensive family of enzymes that control intracellular levels of cAMP and thus regulate T cell responses. It is not known how the function of these enzymes is altered by TCR engagement. We have examined this issue by studying one of the PDE isozymes (PDE4B). PDE4B RNA and protein were detected in resting PBLs, and the levels of PDE4B protein increased with cell cycling. In peripheral blood T cells, two previously reported PDE4B isoforms could be detected: one was 75–80 kDa (PDE4B1) and the other was 65–67 kDa (PDE4B2). These two isoforms differed in their N-terminal sequence, with the presence of four potential myristylation sites in the PDE4B2 that are absent in PDE4B1. Consequently, only PDE4B2 was found in association with the CD3{varepsilon} chain of the TCR. In addition, although both isoforms were phosphorylated in tyrosines in pervanadate-stimulated T cells, only the TCR-associated PDE4B2 was tyrosine-phosphorylated following CD3 ligation. The kinetics of phosphorylation of TCR-associated PDE4B2 correlated with changes in cAMP levels, suggesting that tyrosine phosphorylation of the TCR-associated PDE4B isoform upon engagement of this receptor may be an important regulatory step in PDE4B function. Our results reveal that selectivity of PDE4B activation can be achieved by differential receptor association and phosphorylation of the alternatively spliced forms of this PDE.
https://ir.lib.uwo.ca/immunologypub/50
oai:ir.lib.uwo.ca:immunologypub-1053
2009-12-12T02:00:34Z
publication:mnipub
publication:physpharmpub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:physpharm
publication:mni
publication:robarts
publication:institutes
10090924
Metalloproteinases Are Involved in Lipopolysaccharide- and Tumor Necrosis Factor-alpha-mediated Regulation of CXCR1 and CXCR2 Chemokine Receptor Expression
Khandaker, Masud H.
Mitchell, Gordon
Xu, Luoling
Andrews, Joseph D.
Singh, Rajkumari
Leung, Harry
Madrenas, Joaquín
Ferguson, Stephen S. G.
Feldman, Ross D.
Kelvin, David J.
Article
1999-04-01T08:00:00Z
Antigens
CD
Apoptosis
Calcium Signaling
Chemotaxis
Leukocyte
Dexamethasone
Down-Regulation
Edetic Acid
Endocytosis
GTP-Binding Proteins
Humans
Interleukin-8
Leucine
Leukocytes
Lipopolysaccharides
Metalloendopeptidases
Microscopy
Confocal
Phenanthrolines
Protease Inhibitors
Receptors
Chemokine
Receptors
Interleukin
Receptors
Interleukin-8A
Receptors
Interleukin-8B
Tumor Necrosis Factor-alpha
Blood
Blood
93
7
2173
2185
Immunology and Infectious Disease
The neutrophil-specific G-protein-coupled chemokine receptors, CXCR1 and CXCR2, bind with high affinity to the potent chemoattractant interleukin-8 (IL-8). The mechanisms of IL-8 receptor regulation are not well defined, although previous studies have suggested a process of ligand-promoted internalization as a putative regulatory pathway. Herein, we provide evidence for two distinct processes of CXCR1 and CXCR2 regulation. Confocal microscopy data showed a redistribution of CXCR1 expression from the cell surface of neutrophils to internal compartments after stimulation with IL-8, whereas stimulation with bacterial lipopolysaccharide (LPS) or tumor necrosis factor-alpha (TNF-alpha) did not induce CXCR1 internalization but instead mediated a significant loss of membrane-proximal CXCR1 staining intensity. To investigate whether proteolytic cleavage was the mechanism responsible for LPS- and TNF-alpha-induced downmodulation of IL-8 receptors, we tested a panel of proteinase inhibitors. The downmodulation of CXCR1 and CXCR2 by LPS and TNF-alpha was most dramatically inhibited by metalloproteinase inhibitors; 1, 10-phenanthroline and EDTA significantly attenuated LPS- and TNF-alpha-induced loss of CXCR1 and CXCR2 cell surface expression. Metalloproteinase inhibitors also blocked the release of CXCR1 cleavage fragments into the cell supernatants of LPS- and TNF-alpha-stimulated neutrophils. In addition, while treatment of neutrophils with LPS and TNF-alpha inhibited IL-8 receptor-mediated calcium mobilization and IL-8-directed neutrophil chemotaxis, both 1, 10-phenanthroline and EDTA blocked these inhibitory processes. In contrast, metalloproteinase inhibitors did not affect IL-8-mediated downmodulation of CXCR1 and CXCR2 cell surface expression or receptor signaling. Thus, these findings may provide further insight into the mechanisms of leukocyte regulation during immunologic and inflammatory responses.
https://ir.lib.uwo.ca/immunologypub/49
oai:ir.lib.uwo.ca:surgerypub-1020
2010-01-28T06:24:42Z
publication:mnipub
publication:surgerypub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:surgery
publication:institutes
10188826
Surgical Technique for Vascularized Thymus Transplantation in Mice
Jiang, Jifu
Wang, Hao
Madrenas, Joaquin
Zhong, Robert
Article
1999-01-01T08:00:00Z
Animals
Endocrine Surgical Procedures
Flow Cytometry
Male
Mice
Mice
Inbred BALB C
Microsurgery
Postoperative Period
Random Allocation
Thymus Gland
Time Factors
Microsurgery
19
2
56
60
Medical Immunology
Surgery
Traditionally, mouse nonvascularized thymus implants have been used to investigate various aspects of thymus function. However, these grafts are easily damaged by ischemia and fail to reproduce the normal anatomy of the thymus. In addition, the function of these grafts has not been fully examined. We have recently developed a vascularized thymus transplant model in mice. The donor operation consists of isolating the right lobe of the thymus and creating a single vascular pathway. In the recipient surgery, end-to-side anastomoses between donor brachycephalic artery and recipient right common carotid artery, and between donor superior caval vein and recipient right external jugular vein, were performed. We performed 10 consecutive isografts in BALB/c mice with a success rate of 90%. The thymus grafts had a normal histology and function. This study illustrates that it is technically possible to transplant a mouse vascular thymus graft. This model has several advantages that make it a useful tool to study many aspects of thymus function. We plan to use this model further to study the potential for induction of tolerance by thymus grafts.
https://ir.lib.uwo.ca/surgerypub/22
oai:ir.lib.uwo.ca:mnipub-1015
2010-01-24T07:52:17Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
9480724
Development of an I-Ag7-expressing Antigen-presenting Cell Line: Intrinsic Molecular Defect in Compact I-Ag7 Dimer Generation
Nabavieh, Ali
Chou, Henry
Volokhov, Irina
Lee, James E.
Purdy, Lisa E.
Elliott, John F.
Singh, Bhagirath
Madrenas, Joaquín
Article
1998-02-01T08:00:00Z
Animals
Antigen Presentation
Antigen-Presenting Cells
Cell Culture Techniques
Cell Line
Diabetes Mellitus
Type 1
Dimerization
Epitopes
Glutamate Decarboxylase
Histocompatibility Antigens Class II
Hybridomas
Immunophenotyping
L Cells (Cell Line)
Mice
Mice
Inbred BALB C
Mice
Inbred NOD
T-Lymphocytes
Transfection
Journal of Autoimmunity
Journal of Autoimmunity
11
1
63
71
10.1006/jaut.1997.0176
Immunology and Infectious Disease
Microbiology
Insulin-dependent diabetes mellitus (IDDM) results from chronic, T-cell dependent, autoimmune destruction of the insulin-producing beta-cells in the Langerhans' islets of the pancreas. Non-obese diabetic (NOD) mice spontaneously develop IDDM that resembles human type I diabetes. The susceptibility to diabetes in the NOD strain is a complex polygenic trait that determines a phenotype of immune alterations. The unique MHC class II molecule expressed by NOD mice (I-Ag7) plays a major role in the development of disease. Recently, it has been reported that I-Ag7 molecules generate a lower proportion of compact alphabeta heterodimers, compared to other haplotypes. However, it is not clear whether this reflects an intrinsic defect of this molecule to bind peptide stably or is the result of abnormal processing and/or peptide loading into the I-Ag7 molecule. Our aim was to develop and characterize a suitable antigen-presenting cell (APC) that expressed I-Ag7 in the context of a non-diabetes-prone antigen processing and presentation machinery. Here, we report the generation of a mouse DAP.3 fibroblast cell line (DAP.3Ag7) that constitutively expresses high levels of I-Ag7. Using DAP.3 cells transfected with I-Ag7 or I-Ak, we show that the expression of compact dimers in the same cell type is proportionally less for I-Ag7 molecules than for I-Ak molecules, implying an intrinsic defect of the I-Ag7 molecule as the cause for the low generation of compact dimers. However, DAP.3Ag7 cells are able to process and present antigen, as indicated by I-Ag7-dependent IL-2 production by a GAD67-specific NDO T-cell hybridoma after stimulation with GAD and live, but not fixed, DAP.3Ag7 cells. The IL-2 response to GAD when presented by DAP.3Ag7 was significantly higher than the response to GAD presented by NOD splenocytes. Based on these data, we conclude that the low generations of compact dimers is an intrinsic feature of I-Ag7 molecules and not affected by other genes in the NOD background. The DAP.3Ag7 cell line should be a valuable tool with which to dissect the role of the I-Ag7 molecule in antigen presentation and T-cell activation in NOD mice, which clearly contributes to the development of IDDM.
https://ir.lib.uwo.ca/mnipub/18
oai:ir.lib.uwo.ca:immunologypub-1059
2009-12-12T05:57:31Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:mni
publication:robarts
publication:institutes
9016871
The Efficiency of CD4 Recruitment to Ligand-engaged TCR Controls the Agonist/partial Agonist Properties of Peptide-MHC Molecule Ligands
Madrenas, Joaquín
Chau, Luan A.
Smith, Judy
Bluestone, Jeffrey A.
Germain, Ronald N.
Article
1997-01-20T08:00:00Z
Amino Acid Sequence
Animals
Cell Line
Major Histocompatibility Complex
Mice
Molecular Sequence Data
Peptides
Phosphorylation
Receptors
Antigen
T-Cell
Signal Transduction
Th1 Cells
Journal of Experimental Medicine
Journal of Experimental Medicine
185
2
219
229
Immunology and Infectious Disease
One hypothesis seeking to explain the signaling and biological properties of T cell receptor for antigen (TCR) partial agonists and antagonists is the coreceptor density/kinetic model, which proposes that the pharmacologic behavior of a TCR ligand is largely determined by the relative rates of (a) dissociation ofligand from an engaged TCR and (b) recruitment oflck-linked coreceptors to this ligand-engaged receptor. Using several approaches to prevent or reduce the association of CD4 with occupied TCR, we demonstrate that consistent with this hypothesis, the biological and biochemical consequence of limiting this interaction is to convert typical agonists into partial agonist stimuli. Thus, adding anti-CD4 antibody to T cells recognizing a wild-type peptide-MHC class II ligand leads to disproportionate inhibition of interleukin-2 (IL-2) relative to IL-3 production, the same pattern seen using a TCR partial agonist/antagonist. In addition, T cells exposed to wild-type ligand in the presence of anti-CD4 antibodies show a pattern of TCR signaling resembling that seen using partial agonists, with predominant accumulation of the p21 tyrosine-phosphorylated form of TCR-zeta, reduced tyrosine phosphorylation of CD3epsilon, and no detectable phosphorylation of ZAP-70. Similar results are obtained when the wild-type ligand is presented by mutant class II MHC molecules unable to bind CD4. Likewise, antibody coligation of CD3 and CD4 results in an agonist-like phosphorylation pattern, whereas bivalent engagement of CD3 alone gives a partial agonist-like pattern. Finally, in accord with data showing that partial agonists often induce T cell anergy, CD4 blockade during antigen exposure renders cloned T cells unable to produce IL-2 upon restimulation. These results demonstrate that the biochemical and functional responses to variant TCR ligands with partial agonist properties can be largely reproduced by inhibiting recruitment of CD4 to a TCR binding a wild-type ligand, consistent with the idea that the relative rates of TCR-ligand disengagement and of association of engaged TCR with CD4 may play a key role in determining the pharmacologic properties of peptide-MHC molecule ligands. Beyond this insight into signaling through the TCR, these results have implications for models of thymocyte selection and the use of anti-coreceptor antibodies in vivo for the establishment ofimmunological tolerance.
https://ir.lib.uwo.ca/immunologypub/55
oai:ir.lib.uwo.ca:immunologypub-1058
2009-12-12T05:54:04Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:mni
publication:robarts
publication:institutes
9200439
Inactivation of lck and Loss of TCR-mediated Signaling Upon Persistent Engagement with Complexes of Peptide: MHC Molecules
Lee, J. E.
Cossoy, M. B.
Chau, L. A.
Singh, B.
Madrenas, J.
Article
1997-07-01T07:00:00Z
Amino Acid Sequence
Animals
Clone Cells
Lymphocyte Activation
Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
Major Histocompatibility Complex
Mice
Molecular Sequence Data
Peptides
Receptors
Antigen
T-Cell
Signal Transduction
T-Lymphocytes
src-Family Kinases
Journal of Immunology
Journal of Immunology
159
1
61
69
Immunology and Infectious Disease
T cell activation follows recognition of specific peptide:MHC molecule complexes in the context of proper costimulation. The earliest detectable event in T cell activation, within seconds of TCR ligand recognition, is tyrosine phosphorylation of TCR subunits. This causes a cascade of events leading to up-regulation of gene transcription that will drive T cell proliferation and differentiation. Regulation of TCR-mediated signaling upon T cell commitment is unclear. Here, we report that persistent stimulation of T cells, beyond 10 min, correlated with a reversible decrease in tyrosine phosphorylation of T cell lysates that did not affect T cell commitment to proliferation. Loss of Ag-induced tyrosine phosphorylation was not due to lack of Ag presentation, loss of TCR expression, or T cell death, but, rather, it was associated with a lack of TCR subunit tyrosine phosphorylation. We termed this phenomenon TCR desensitization by analogy to the loss of signaling observed in other receptor systems upon persistent engagement with agonist ligands. TCR desensitization correlated with surface reexpression of TCR without concomitant reexpression of coreceptor molecules. Biochemically, TCR desensitization correlated with increased levels of serine-phosphorylated lck, loss of lck kinase activity, and reversible loss of cytosolic lck. Thus, TCR signaling is regulated by desensitization that may be due to serine phosphorylation of lck causing inactivation and loss of this src kinase. This may have important implications by preventing TCR signaling and activation-induced cell death once the T lymphocyte is committed to proliferate.
https://ir.lib.uwo.ca/immunologypub/54
oai:ir.lib.uwo.ca:immunologypub-1057
2009-12-12T05:49:24Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
9476651
Differential Signaling through the T Cell Receptor: From Biochemistry to Transplantation Tolerance
Madrenas, J.
Lazarovits, A. I.
Article
1998-01-01T08:00:00Z
Animals
Antigens
CD4
Antigens
CD45
Antigens
CD8
Clonal Anergy
Humans
Receptors
Antigen
T-Cell
Signal Transduction
Histology and Histopathology
Histology and Histopathology
13
1
221
229
Immunology and Infectious Disease
Recent advances in our understanding of the structural nature of T cell activation and signal transduction from the T cell receptor for antigen make possible the development of new tolerogenic strategies. Here, we summarize the evidence supporting a critical role for the co-receptor molecule (CD4 or CD8) and CD45 in determining the pattern of T cell receptor-mediated signaling. The consequences of this differential signaling can range from T cell proliferation and cytokine production to the establishment of a state of proliferative unresponsiveness known as T cell anergy. Inducing T cell anergy can be an alternative approach for the establishment of transplantation tolerance.
https://ir.lib.uwo.ca/immunologypub/53
oai:ir.lib.uwo.ca:immunologypub-1055
2009-12-12T02:33:10Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
9584148
Dissociation of Intracellular Signaling Pathways in Response to Partial Agonist Ligands of the T Cell Receptor
Chau, Luan A.
Bluestone, Jeffrey A.
Madrenas, Joaquin
Article
1998-05-18T07:00:00Z
Animals
Antigens
CD4
Clone Cells
Ligands
Mice
Phosphorylation
Protein-Tyrosine Kinases
Receptors
Antigen
T-Cell
Signal Transduction
T-Lymphocytes
ZAP-70 Protein-Tyrosine Kinase
Journal of Experimental Medicine
Journal of Experimental Medicine
187
10
1699
1709
10.1084/jem.187.10.1699
Immunology and Infectious Disease
The T cell receptor (TCR) is a versatile receptor able to generate different signals that result in distinct T cell responses. The pattern of early signals is determined by the TCR binding kinetics that control the ability of the ligand to coengage TCR and coreceptor. Coengagement of TCR and CD4 results in an agonist signaling pattern with complete tyrosine phosphorylation of TCR subunits, and recruitment and activation of ZAP-70. In contrast, TCR engagement without CD4 coengagement causes a partial agonist type of signaling, characterized by distinct phosphorylation of TCR subunits and recruitment but no activation of ZAP-70. The pathways triggered by partial agonist signaling are unknown. Here, we show that agonists cause association of active lck and active ZAP-70 with p120-GTPase-activating protein (p120-GAP). These associations follow engagement of CD4 or CD3, respectively. In contrast, partial agonists do not activate lck or ZAP-70, but induce association of p120-GAP with inactive ZAP-70. Despite these differences, both agonist and partial agonist signals activate the mitogen-activated protein kinase (MAPK) pathway. However, MAPK activation by partial agonists is transient, supporting a kinetic, CD4-dependent model for the mechanism of action of variant TCR ligands. Transient MAPK activation may explain some of the responses to TCR partial agonists and antagonists.
https://ir.lib.uwo.ca/immunologypub/51
oai:ir.lib.uwo.ca:immunologypub-1056
2009-12-12T05:43:49Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
9785671
T-cell Anergy and Altered T-cell Receptor Signaling: Effects on Autoimmune Disease
Salojin, Konstantin V.
Zhang, Jian
Madrenas, Joaquin
Delovitch, Terry L.
Article
1998-10-01T07:00:00Z
Animals
Autoimmune Diseases
Clonal Anergy
Humans
Mice
Mice
Inbred BALB C
Mice
Inbred NOD
Receptors
Antigen
T-Cell
T-Lymphocytes
Immunology Today
Immunology Today
19
10
468
473
10.1016/S0167-5699(98)01326-7
Immunology and Infectious Disease
Immunological self-tolerance can be acquired by several mechanisms, including the induction of anergy in autoreactive T cells. In this sense, anergy is predictably advantageous for the immune system. Here, Konstantin Salojin and colleagues present an alternative view that the induction of anergy in regulatory T cells may be harmful to the host and elicit autoimmune disease.
https://ir.lib.uwo.ca/immunologypub/52
oai:ir.lib.uwo.ca:surgerypub-1021
2010-01-28T06:30:40Z
publication:mnipub
publication:surgerypub
publication:pmid
publication:immunologypub
publication:faculties
publication:mni
publication:robarts
publication:surgery
publication:institutes
9203977
Generation of Dendritic Cell-like Antigen-presenting Cells in Long-term Mixed Leucocyte Culture: Phenotypic and Functional Studies
Gao, J. X.
Madrenas, J.
Zeng, W.
Zhong, R.
Grant, D.
Article
1997-05-01T07:00:00Z
Animals
Antigen Presentation
Cell Division
Cell Movement
Cell Separation
Cytokines
Dendritic Cells
Flow Cytometry
Immunophenotyping
Isoantigens
Lymphocyte Culture Test
Mixed
Lymphoid Tissue
Male
Mice
Mice
Inbred BALB C
Mice
Inbred C3H
Mice
Inbred C57BL
Immunology
91
1
135
144
10.1046/j.1365-2567.1997.00220.x
Medical Immunology
Surgery
The mechanisms contributing to the proliferation and differentiation of antigen-presenting cell (APC) precursors upon antigen stimulation or tissue injury are poorly understood. Herein, we report the induction of a population of dendritic cell-like cells (DLC) with potent antigen-presentation function from unfractionated spleen cells by means of repetitive allostimulation in long-term mixed leucocyte cultures (LT-MLC). Initially, only a few adherent DLC were observed. By 4-6 weeks, however, there were large numbers of DLC which survived persistently. Features of these DLC are closely related to dendritic cells (DC), including (1) dendritic, veiled or spiny-processed morphology; (2) expression of a wide array of leucocyte surface markers including DC-associated or restricted antigens: 33D1, NLDC-145, CD11c (N418), heat-stable antigen (HSA), CD44, B7-1 and B7-2; (3) ability to migrate to draining lymph nodes and white pulp area of spleen; (4) expression of high level of major histocompatability complex (MHC) class II molecules and (5) more potent mixed leucocyte reaction (MLR)-stimulating capacity than peritoneal macrophages and APC-enriched spleen cells. DLC-stimulated MLR was inhibited by monoclonal antibodies (mAbs) to B7-1, B7-2, intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), leucocyte-function associated antigen-1 (LFA-1) or very-late activation antigen-4 (VLA-4) by 30-55%. When maintained for more than 2 months, the DLC did not lose their MLR-stimulating activity, but many surface markers were down-regulated except for Mac-2 and VCAM-1, which remained stable or were up-regulated, respectively. In short-term culture, the addition of granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin (IL)-2 enhanced proliferation of DLC, while tumour necrosis factor-alpha (TNF-alpha) and IL-4 did not. IL-4 suppressed not only 'spontaneous', but also GM-CSF-enhanced proliferation, suggesting that cytokines play a differential role in DLC proliferation. These results confirm that professional APC can proliferate in response to repetitive antigen stimulation, and their proliferation is differentially regulated by cytokines. A comparison study of DLC with typical DC is being carried out in our laboratory.
https://ir.lib.uwo.ca/surgerypub/23
oai:ir.lib.uwo.ca:immunologypub-1060
2009-12-12T06:03:14Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:mni
publication:robarts
publication:institutes
8790400
Interleukin 2 Production, Not the Pattern of Early T-cell Antigen Receptor-dependent Tyrosine Phosphorylation, Controls Anergy Induction by Both Agonists and Partial Agonists
Madrenas, J.
Schwartz, R. H.
Germain, R. N.
Article
1996-09-03T07:00:00Z
Animals
Cell Division
Clonal Anergy
Histocompatibility Antigens Class II
Interleukin-2
L Cells (Cell Line)
Mice
Phenotype
Phosphorylation
Protein-Tyrosine Kinases
Receptors
Antigen
T-Cell
Signal Transduction
Th1 Cells
Tyrosine
Proceedings of the National Academy of Sciences of the United States of America
Proceedings of the National Academy of Sciences of the United States of America
93
18
9736
9741
Immunology and Infectious Disease
Full activation of T cells requires signaling through the T-cell antigen receptor (TCR) and additional surface molecules interacting with ligands on the antigen-presenting cell. TCR recognition of agonist ligands in the absence of accessory signals frequently results in the induction of a state of unresponsiveness termed anergy. However, even in the presence of costimulation, anergy can be induced by TCR partial agonists. The unique pattern of early receptor-induced tyrosine phosphorylation events induced by partial agonists has led to the hypothesis that altered TCR signaling is directly responsible for the development of anergy. Here we show that anergy induction is neither correlated with nor irreversibly determined by the pattern of early TCR-induced phosphorylation. Rather, it appears to result from the absence of downstream events related to interleukin 2 receptor occupancy and/or cell division. This implies that the anergic state can be manipulated independently of the precise pattern of early biochemical changes following TCR occupancy, a finding with implications for understanding the induction of self-tolerance and the use of partial agonist ligands in the treatment of autoimmune diseases.
Dr. Joaquin Madrenas is currently a faculty member at The University of Western Ontario.
https://ir.lib.uwo.ca/immunologypub/56
oai:ir.lib.uwo.ca:immunologypub-1061
2011-07-07T19:44:21Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:mni
publication:robarts
publication:institutes
8920243
Variant TCR Ligands: New Insights into the Molecular Basis of Antigen-dependent Signal Transduction and T-cell Activation
Madrenas, Joaquín
Germain, Ronald N.
Article
1996-04-01T08:00:00Z
Animals
Antigens
Humans
Ligands
Lymphocyte Activation
Receptors
Antigen
T-Cell
Signal Transduction
T-Lymphocytes
Seminars in Immunology
Seminars in Immunology
8
2
83
101
http://dx.doi.org/10.1006/smim.1996.0011
Immunology and Infectious Disease
<p>Recent studies have identified peptide-MHC molecule ligands of alpha beta T-cell receptors with properties apparently distinct from classical agonists. These complexes, which are slight structural variants of the immunizing peptide or original presenting MHC molecule, have several novel properties. They can act as partial agonists able to induce only some and not other effector activities of the T cell, as antagonists able to inhibit T-cell functions stimulated by agonist ligand, or as mixed partial agonists/antagonists. Here we discuss the existing data suggesting that a simple receptor occupancy model does not account for the properties of these TCR ligands and review emerging data on qualitative differences in signal transduction following TCR engagement by priming versus variant complexes. We propose several non-exclusive models to explain both the biochemical and biological properties of variant ligands with partial agonist or antagonist properties.</p>
<p>Dr. Joaquin Madrenas was not affiliated with The University of Western Ontario at the time of publication.</p>
https://ir.lib.uwo.ca/immunologypub/57
oai:ir.lib.uwo.ca:immunologypub-1062
2011-04-19T22:48:26Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:mni
publication:robarts
publication:institutes
7824949
Zeta Phosphorylation without ZAP-70 Activation Induced by TCR Antagonists or Partial Agonists
Madrenas, J.
Wange, R. L.
Wang, J. L.
Isakov, N.
Samelson, L. E.
Germain, R. N.
Article
1995-01-27T08:00:00Z
Amino Acid Sequence
Animals
Clone Cells
Cytochrome c Group
Enzyme Activation
Histocompatibility Antigens Class II
Interleukin-2
L Cells (Cell Line)
Ligands
Lymphocyte Activation
Membrane Proteins
Mice
Molecular Sequence Data
Mutation
Peptide Fragments
Phosphorylation
Protein-Tyrosine Kinases
Receptors
Antigen
T-Cell
Signal Transduction
T-Lymphocytes
Helper-Inducer
Tyrosine
ZAP-70 Protein-Tyrosine Kinase
Science
Science
267
5197
515
518
http://dx.doi.org/10.1126/science.7824949
Immunology and Infectious Disease
<p>Small changes in the peptide-major histocompatibility complex (MHC) molecule ligands recognized by antigen-specific T cell receptors (TCRs) can convert fully activating complexes into partially activating or even inhibitory ones. This study examined early TCR-dependent signals induced by such partial agonists or antagonists. In contrast to typical agonist ligands, both an antagonist and several partial agonists stimulated a distinct pattern of zeta chain phosphorylation and failed to activate associated ZAP-70 kinase. These results identify a specific step in the early tyrosine phosphorylation cascade that is altered after TCR engagement with modified peptide-MHC molecule complexes. This finding may explain the different biological responses to TCR occupancy by these variant ligands.</p>
<p>Dr. Joaquin Madrenas is currently a faculty member at The University of Western Ontario.</p>
https://ir.lib.uwo.ca/immunologypub/58
oai:ir.lib.uwo.ca:immunologypub-1063
2009-12-12T06:16:06Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:mni
publication:robarts
publication:institutes
8084339
Alternatively Spliced, Germline Jα11-2-Cα mRNAs Are the Predominant T Cell Receptor α Transcripts in Mouse Kidney
Madrenas, Joaquín
Vincent, Dianne H.
Kriangkum, Jitra
Elliott, John F.
Halloran, Philip F.
Article
1994-09-01T07:00:00Z
Alternative Splicing
Amino Acid Sequence
Animals
Base Sequence
Cloning
Molecular
Cytoplasm
Female
Kidney
Male
Mice
Mice
Inbred Strains
Molecular Sequence Data
Polymerase Chain Reaction
RNA
Messenger
Receptors
Antigen
T-Cell
alpha-beta
Molecular Immunology
Molecular Immunology
31
13
993
1004
10.1016/0161-5890(94)90094-9
Immunology and Infectious Disease
We recently reported the expression of a truncated T cell receptor (TCR) α mRNA in kidney and brain of normal mice. In the kidney, the truncated TCR α transcript was expressed by bone marrow-dependent, non-T large interstitial cells located predominantly in the medulla. Here, we report the molecular characterization of the truncated TCR α transcript from kidney. Using a modified anchored-PCR (A-PCR) technique and directional cloning, 37 cDNA clones extending 5' of the Cα region were generated. cDNA sequencing showed that 29 of the clones (78%) originated in the Jα 11-2 region. Of these clones, 17 started upstream or in the Jα 11-2 exon and contained the entire Jα 11-2 sequence correctly spliced to the first Cα exon. Analysis of the sequence revealed the presence of multiple stop codons in all three reading frames. The other 12 clones originated further upstream of the Jα 11-2 exon and did not include the Jα 11-2 exon, but rather arose from the joining of a cryptic splice donor signal to the usual TCR α C splice acceptor. This alternatively spliced transcript contained an open reading frame extending from the upstream Jα 11-2 region to 82 nucleotides downstream of the beginning of the TCR C α region, and potentially encoded a 36 amino acid polypeptide. The remaining eight clones all contained the Jα TA61 region correctly spliced to Cα with two of these extending upstream of the Jα TA61 exon. The predominance of Jα 11-2-Cα containing clones was confirmed by RNase protection assay using total RNA from kidney and spleen of scid mice. The 3' region of the transcript contained a fully conserved, correctly spliced TCR α C region which was polyadenylated at the 3' end. The truncated TCR a mRNA could be detected in preparations of cytoplasmic RNA, indicating that this transcript follows a normal RNA processing pathway. Our results demonstrate that the truncated TCR α mRNA expressed in normal mouse kidney is a germline J-C transcript resulting from transcription initiated predominantly upstream of the Jα 11-2 region. This germline transcript in the kidney is undergoing alternative splicing leading to the appearance of an open reading frame coding for a short polypeptide. These results suggest that the product of this transcript may be functionally relevant.
Dr. Joaquin Madrenas is currently a faculty member at The University of Western Ontario.
https://ir.lib.uwo.ca/immunologypub/59
oai:ir.lib.uwo.ca:immunologypub-1064
2009-12-12T06:19:51Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:mni
publication:robarts
publication:institutes
8305641
Ly-6 in Kidney Is Widely Expressed on Tubular Epithelium and Vascular Endothelium and Is Up-regulated by Interferon Gamma
Blake, P. G.
Madrenas, J.
Halloran, P. F.
Article
1993-11-01T08:00:00Z
Animals
Antigens
Ly
Base Sequence
DNA
DNA Probes
Endothelium
Vascular
Epithelium
Female
Gene Expression
Humans
Interferon-gamma
Recombinant
Kidney
Kidney Tubules
Membrane Proteins
Mice
Mice
Inbred Strains
Mice
Mutant Strains
Molecular Sequence Data
Nephritis
Tissue Distribution
Up-Regulation
Journal of the American Society of Nephrology
Journal of the American Society of Nephrology
4
5
1140
1150
Immunology and Infectious Disease
Ly-6 is a multigene family of murine polymorphic cell membrane proteins that are glycosydlphosphatidylinositol anchored, widely expressed on lymphoid tissue, and homologous to the recently described human CD59. An unexpected feature of Ly-6 is its high level of expression in the kidney. This renal expression and its interferon (IFN)-gamma inducibility in murine strains expressing different Ly-6 haplotypes were studied with monoclonal antibodies and cDNA probes that recognize Ly-6A/E and Ly-6C. Ly-6 expression was much more extensive in the kidney than in other parenchymal organs. Ly-6A.1/E.2 was extensively expressed on vascular endothelium and on tubular epithelium, particularly in the distal nephron. Pattern of expression differed between strains expressing A and E alleles. Ly-6C was not detected by monoclonal antibodies but was detected by oligonucleotide-specific probes. Treatment with recombinant IFN-gamma or IFN-inducing agents increased Ly-6 expression markedly, particularly on the luminal aspect of the proximal tubular epithelium, where Ly-6A/E became prominent. This luminal expression is typical for glycosydlphosphatidylinositol-anchored proteins but contrasts with that of other molecules, such as major histocompatibility classes I and II, which are generally expressed on the basolateral surface of the tubular epithelium. Up-regulation occurred within 6 h of IFN-gamma treatment and returned to normal by 48 h. Similar up-regulation of Ly-6 was seen in murine lupus nephritis and in mercuric chloride nephropathy. The characteristics of renal Ly-6, such as its IFN-gamma responsiveness, endothelial and tubular expression, polymorphism, strong antigenicity, and possible allelic regulation, make it a candidate to be a target molecule in alloresponses. The renal expression of Ly-6 is similar to that of CD59 in the human kidney, supporting the suggestion that these proteins are closely related.
Dr. Joaquin Madrenas is currently a faculty member at The University of Western Ontario.
https://ir.lib.uwo.ca/immunologypub/60
oai:ir.lib.uwo.ca:immunologypub-1066
2009-12-12T21:58:04Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:mni
publication:robarts
publication:institutes
1487321
Complement-dependent Cytotoxicity for Negative Selection at the mRNA Level
Gill, N. S.
Madrenas, J.
Halloran, P. F.
Article
1992-12-01T08:00:00Z
Antibodies
Monoclonal
Antigens
CD3
Blotting
Northern
Cell Count
Complement System Proteins
Cytotoxicity
Immunologic
Histocompatibility Antigens Class I
Humans
RNA
Messenger
RNA
Ribosomal
18S
RNA
Ribosomal
28S
Receptors
Antigen
T-Cell
alpha-beta
Immunological Investigations
Immunological Investigations
21
7
629
635
10.3109/08820139209069399
Immunology and Infectious Disease
Complement-Dependent Cytotoxicity (CDC) is a common technique used for isolating and characterizing cell populations. However, the molecular events resulting from CDC-mediated cell injury remain obscure. In order to use CDC as a selection procedure for studies at the RNA level, we examined if CDC is associated with rapid degradation of RNAs from target cells without affecting the stability and viability of RNAs of non-target cells. Using a model of anti-CD3-mediated CDC, we show that T cell-specific RNAs were absent immediately after CDC. However, ribosomal RNAs and mRNAs from non-targeted cells (non-T cells) were not affected by CDC. Our results indicate that CDC is associated with rapid degradation of only target cell RNAs, validating CDC as a method for cell isolation without interfering with further studies at the RNA level.
Dr. Joaquin Madrenas is currently a faculty member at The University of Western Ontario.
https://ir.lib.uwo.ca/immunologypub/62
oai:ir.lib.uwo.ca:immunologypub-1065
2009-12-12T21:54:35Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:mni
publication:robarts
publication:institutes
8081760
The Molecular Immunology of Acute Rejection: An Overview
Halloran, Philip F.
Broski, Anthony P.
Batiuk, Thomas D.
Madrenas, Joaquín
Article
1993-03-01T08:00:00Z
Acute Disease
Animals
Cell Adhesion Molecules
Cytokines
Graft Rejection
Histocompatibility Antigens
Humans
Immunoglobulins
T-Lymphocytes
Transplantation Immunology
Transplant Immunology
Transplant Immunology
1
1
3
27
10.1016/0966-3274(93)90055-D
Immunology and Infectious Disease
Transplantation immunology began as an empirical science but can now take its place as a discipline with a strong theoretical and molecular basis. The Laws of Transplantation, formulated at the beginning of this century by Little and Tyzzer, can be paraphrased as ‘Isografts succeed; allografts fail’. As the century closes, the molecular basis of those laws is emerging. Achieving the full potential of the advances in immunology requires that transplant clinicians learn the molecular basis for their art and participate in the development and testing of new hypotheses; and that immunologists assess their ideas against the real world of the transplant recipient. This review will highlight areas of recent progress in transplant immunology and point out areas where clinical events remain poorly explained. Because many excellent reviews are available, we will primarily quote articles after 1990. Our approach to transplantation biology at the molecular level is summarized in Table 1.
Dr. Joaquin Madrenas is currently a faculty member at The University of Western Ontario.
https://ir.lib.uwo.ca/immunologypub/61
oai:ir.lib.uwo.ca:immunologypub-1068
2009-12-12T22:04:51Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:mni
publication:robarts
publication:institutes
1825860
Interferon Gamma-mediated Renal MHC Expression in Mercuric Chloride-induced Glomerulonephritis
Madrenas, Joaquín
Parfrey, Nollaig A.
Halloran, Philip F.
Article
1991-02-01T08:00:00Z
Animals
Female
Gene Expression Regulation
Glomerulonephritis
Immune Complex Diseases
Immunoenzyme Techniques
Interferon-gamma
Kidney
Kidney Glomerulus
Major Histocompatibility Complex
Male
Mercuric Chloride
Mice
Mice
Inbred Strains
RNA
Messenger
Kidney International
Kidney International
39
2
273
281
10.1038/ki.1991.33
Immunology and Infectious Disease
Interferon gamma-mediated renal MHC expression in mercuric chloride-induced glomerulonephritis. In rodents, mercuric chloride (HgCl2) causes an autoimmune disorder with glomerulonephritis (GN), and represents an animal model for the pathogenesis of GN. We have tested the hypothesis that HgCl2 induces major histocompatibility complex (MHC) expression in renal parenchymal cells, and studied the kinetics of this induction and its temporal relation to the development of immune complex deposition in the glomeruli. Mice treated with doses of HgCl2 between 2 and 3.2 mg/kg three times for one week had increased renal expression of MHC class I and class II (at the mRNA and the product levels). Class I induction was observed in proximal tubule cells, endothelial cells and glomerular cells. Class II induction was seen mainly in interstitial cells and, to a lesser extent, in tubule cells. Rénal MHC expression was maximal at one week, decreased progressively after the second week of HgCl2 administration, and reached basal levels by 23 weeks. In contrast, the amount of lymphocyte infiltration in the kidney increased from the first to the fifth week and was followed by the appearance of glomerular immune deposits from the third week on. Glomerular immune complex deposits were maximal at five weeks and, by 23 weeks, immune deposits in HgCl2-treated mice were only slightly increased over those observed in the sham group. Renal MHC induction by HgCl2 was significantly reduced by treatment with monoclonal antibody against interferon gamma. Our results indicate that, in the early phase of HgCl2-induced GN, there is induction of expression for MHC class I and II products, mediated by interferon-gamma (INF-gamma), and raise the possibility that the induction of MHC expression or other changes in gene expression induced by INF-gamma may be involved in the later development of autoimmune renal injury.
Dr. Joaquin Madrenas is currently a faculty member at The University of Western Ontario.
https://ir.lib.uwo.ca/immunologypub/64
oai:ir.lib.uwo.ca:immunologypub-1069
2009-12-12T22:06:24Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:mni
publication:robarts
publication:institutes
1711939
The Mechanism of Action of Cyclosporine: A Perspective for the 90's
Halloran, Philip F.
Madrenas, Joaquín
Article
1991-02-01T08:00:00Z
Amino Acid Isomerases
Anti-Bacterial Agents
Carrier Proteins
Cyclosporins
Drug Resistance
Humans
Lymphocyte Activation
Peptidylprolyl Isomerase
T-Lymphocytes
Tacrolimus
Clinical Biochemistry
Clinical Biochemistry
24
1
3
7
10.1016/0009-9120(91)90063-K
Immunology and Infectious Disease
The introduction of cyclosporine (CyA) as a pharmacological agent has resulted not only in a dramatic improvement in the clinical management of transplant recipients but also in a better understanding of the molecular basis of the immune response, especially T cell function. Knowledge of the mechanism of action of CyA has led to exciting areas of study. Among these are the sequence of regulatory events leading to T cell activation, the potential relevance of isomerases in signal transduction pathways (as the receptor for CyA, cyclophilin has been shown to be an isomerase), the blocking effect of CyA on the development of multidrug resistance, and the striking parallelism between CyA and the newer immunosuppressive agent FK-506. These fields promise to be relevant in solving some of the crucial questions in transplantation immunology, and developing better strategies for immunosuppression.
Dr. Joaquin Madrenas is currently a faculty member at The University of Western Ontario.
https://ir.lib.uwo.ca/immunologypub/65
oai:ir.lib.uwo.ca:immunologypub-1070
2009-12-12T22:08:19Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:mni
publication:robarts
publication:institutes
2238047
Regulation of MHC Transcription
Halloran, Philip F.
Madrenas, Joaquín
Article
1990-11-01T08:00:00Z
Animals
Base Sequence
Gene Expression Regulation
Humans
Major Histocompatibility Complex
Molecular Sequence Data
RNA Processing
Post-Transcriptional
Transcription
Genetic
Transplantation Immunology
Transplantation
Transplantation
50
5
725
738
Immunology and Infectious Disease
Dr. Joaquin Madrenas is currently a faculty member at The University of Western Ontario.
https://ir.lib.uwo.ca/immunologypub/66
oai:ir.lib.uwo.ca:immunologypub-1067
2009-12-12T22:00:58Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:mni
publication:robarts
publication:institutes
1530865
Thymus-independent Expression of a Truncated T Cell Receptor-alpha mRNA in Murine Kidney
Madrenas, J.
Pazderka, F.
Parfrey, N. A.
Halloran, P. F.
Article
1992-01-15T08:00:00Z
Animals
Base Sequence
Blotting
Northern
DNA Nucleotidyltransferases
Female
Integrases
Kidney
Killer Cells
Natural
Male
Mice
Mice
Inbred BALB C
Mice
Inbred CBA
Molecular Sequence Data
RNA
Messenger
Receptors
Antigen
T-Cell
alpha-beta
Recombinases
T-Lymphocytes
Thymus Gland
Transcription
Genetic
Journal of Immunology
Journal of Immunology
148
2
612
619
Immunology and Infectious Disease
During studies on gene expression in the kidney, we unexpectedly observed that murine kidney expresses a truncated form of TCR-alpha mRNA (1.3-1.4 kb). This transcript was not associated with the presence of complete TCR-alpha mRNA (1.7 kb) or detectable TCR-beta or -delta transcripts, thus indicating that the truncated TCR-alpha mRNA could not be attributed to blood contamination of the kidney RNA preparation. The truncated TCR-alpha message appeared to contain at least the C alpha region, as suggested by hybridization with an intra-C alpha 24 oligonucleotide probe, by amplification of the C alpha region with the polymerase chain reaction from total kidney mRNA, and by sequencing of, and hybridization with, the amplified products. In situ hybridization of kidney sections indicated that the transcript was expressed in interstitial cells. Northern blots of cortex and medulla RNA showed that the cells expressing the truncated TCR-alpha mRNA were predominantly located in the medulla. To investigate the possibility that the transcript was not produced by T cells or NK cells, fractionation of renal cell suspensions were performed. The truncated TCR-alpha mRNA was detected in a fraction containing large (low buoyant density) cells in which no expression of CD3, Thy 1, or NK-1.1 was detected, indicating that these cells are not mature T cells, do not express a functional TCR, and are not NK cells. The cells expressing the truncated TCR-alpha mRNA were radiosensitive, and were not thymus dependent, because this transcript was as abundant in nude mice as in normal mice. The transcript was not detected in bone marrow. Expression of the truncated TCR-alpha mRNA was not dependent on an intact recombinase activity as its expression was not affected by the severe combined immunodeficiency mutation. Our results show that murine kidney contains a population of radiosensitive thymus-independent large interstitial cells that express a truncated TCR-alpha mRNA that is not associated with surface expression of functional TCR. These cells may have attempted to rearrange TCR-alpha genes, suggesting that they may be related to the lymphoid lineage.
Dr. Joaquin Madrenas is currently a faculty member at The University of Western Ontario.
https://ir.lib.uwo.ca/immunologypub/63
oai:ir.lib.uwo.ca:immunologypub-1072
2009-12-12T22:10:47Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:mni
publication:robarts
publication:institutes
3057883
An Alternative Approach for Statistical Analysis of Kidney Transplant Data: Multivariate Analysis of Single-center Experience
Madrenas, J.
Newman, S.
McGregor, J. R.
Kovithavongs, T.
Lakey, W. H.
Dossetor, J. B.
Halloran, P. F.
Article
1988-12-01T08:00:00Z
Adult
Age Factors
Cyclosporins
Data Interpretation
Statistical
Female
Graft Survival
Histocompatibility
Humans
Immunosuppressive Agents
Kidney Transplantation
Male
Middle Aged
Statistics as Topic
Tissue Donors
American Journal of Kidney Diseases
American Journal of Kidney Diseases
12
6
524
530
Immunology and Infectious Disease
To avoid the center effect and the possible hidden interactions of multicenter studies, the validity of the Cox Proportional Hazards Model for the analysis of a single-center kidney transplant program was tested, considering 287 renal transplants performed in a 10-year period. The inclusion of type of donor and main immunosuppressive drug as covariates in the model did not violate the proportionality assumption of the Cox model. According to this method, the following covariates were significant in predicting graft survival: cyclosporine, type of donor, good human leukocyte antigen (HLA)-A and HLA-B match (DR data were not considered), highest percentage of reactive antibodies against panel cells, and nephroangiosclerosis as a primary renal disease. Cyclosporine did not significantly improve graft survival in living related donor transplants. Pretransplant blood transfusions, cold ischemia time, and donor ABO blood group were initially significant but dropped out in the step-down procedure. Recipient's age at transplant, cyclosporine, HLA-A and HLA-B match, and nephroangiosclerosis were significant in predicting patient survival. It was concluded that using long-term data of cadaveric and living related renal transplants either on azathioprine or cyclosporine is a valid way to perform multivariate analysis of single-center transplant programs that do not have large samples.
Dr. Joaquin Madrenas is currently a faculty member at The University of Western Ontario.
https://ir.lib.uwo.ca/immunologypub/67
oai:ir.lib.uwo.ca:immunologypub-1074
2009-12-13T13:57:30Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:mni
publication:robarts
publication:institutes
3811858
Extra-Uterine Muumlllerian Carcinosarcoma
Campins, Magda
Madrenas, Joaquin
Biosca, Mercedes
Salas, Antonio
Tallada, Natalia
García-Bragado, Fernando
Article
1986-01-01T08:00:00Z
Carcinosarcoma
Endometriosis
Female
Humans
Middle Aged
Neoplasm Seeding
Pelvic Neoplasms
Time Factors
Acta Obstetricia et Gynecologica Scandinavica
Acta Obstetricia et Gynecologica Scandinavica
65
7
811
812
10.3109/00016348609161510
Immunology and Infectious Disease
Carcinosarcoma of the Müllerian system is an uncommon tumor. We report here a case of extra-uterine carcinosarcoma from pelvic wall, presenting 11 years after hysterectomy. Accidental surgical implantation of endometrioid cells is suggested as the pathogenic mechanism in this case.
Dr. Joaquin Madrinas is currently a faculty member at the University of Western Ontario.
https://ir.lib.uwo.ca/immunologypub/68
oai:ir.lib.uwo.ca:immunologypub-1075
2009-12-13T14:03:11Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:mni
publication:robarts
publication:institutes
3736742
Digoxin-like Immunoreacting Activity in the Serum of Patients on Regular Hemodialysis
Madrenas, J.
Codina, S.
Monné, J.
García-Lucena, M. V.
Rodríguez, J. A.
Ferrer, E.
Piera, L.
Letter to the Editor
1986-01-01T08:00:00Z
Adolescent
Adult
Aged
Digoxin
Female
Humans
Kidney Failure
Chronic
Male
Middle Aged
Radioimmunoassay
Renal Dialysis
Nephron
Nephron
43
4
303
304
10.1159/000183859
Immunology and Infectious Disease
Dr. Joaquin Madrenas is currently a faculty member at The University of Western Ontario.
https://ir.lib.uwo.ca/immunologypub/69
oai:ir.lib.uwo.ca:immunologypub-1076
2009-12-13T14:07:33Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:mni
publication:robarts
publication:institutes
3970493
Carcinoid Tumor, Atrophic Gastritis, and Iron Deficiency Anemia
Biosca, Mercedes
Garcia-Bragado, Fernando
de la Figuera, Mariano
Madrenas, Joaquin
Salas, Antonio
Letter to the Editor
1985-03-01T08:00:00Z
Anemia
Hypochromic
Carcinoid Tumor
Female
Gastritis
Gastritis
Atrophic
Humans
Middle Aged
Paraneoplastic Syndromes
Stomach Neoplasms
Annals of Internal Medicine
Annals of Internal Medicine
102
3
416
417
Immunology and Infectious Disease
Dr. Joaquin Madrenas is currently a faculty member at the University of Western Ontario
https://ir.lib.uwo.ca/immunologypub/70
oai:ir.lib.uwo.ca:immunologypub-1078
2010-01-25T00:58:54Z
publication:mnipub
publication:immunologypub
publication:faculties
publication:mni
publication:robarts
publication:institutes
Hepatitis Toxica por Sales de Oro
Madrenas, Puig J.
Lu Cortez, L.
Allende, E.
Muniz Garcia, R.
Lience, E.
Article
1984-01-01T08:00:00Z
Revista Española de Reumatología
Revista Española de Reumatología
11
115
Immunology and Infectious Disease
This article is not available online here, but the journal in which it was published may be available in Western Libraries. Please use the Shared Library Catalogue's <a href="http://alpha.lib.uwo.ca/">Advanced Search</a> to check our collections.<br>
Dr. Joaquin Madrenas is currently a faculty member at The University of Western Ontario.
https://ir.lib.uwo.ca/immunologypub/72
oai:ir.lib.uwo.ca:immunologypub-1077
2010-01-25T00:59:50Z
publication:mnipub
publication:immunologypub
publication:faculties
publication:mni
publication:robarts
publication:institutes
Polimiositis y Carcinoma Pulmonar
Madrenas, Puig J.
Padro, Ubeda L.
Codina, Puiggros A.
Article
1984-10-27T07:00:00Z
Medicina Clínica
Medicina Clínica
83
561
562
Immunology and Infectious Disease
This article is not available online here, but the journal in which it was published may be available in Western Libraries. Please use the Shared Library Catalogue's <a href="http://alpha.lib.uwo.ca/">Advanced Search</a> to check our collections.<br>
Dr. Joaquin Madrenas is currently a faculty member at The University of Western Ontario.
https://ir.lib.uwo.ca/immunologypub/71
oai:ir.lib.uwo.ca:immunologypub-1081
2010-01-24T23:56:18Z
publication:mnipub
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
Partial Recovery of Renal Function in an Oliguric Patient Affected with Goodpasture's Syndrome after Treatment with Steroids, Immunosuppressives, and Plasmapheresis
Fort, J.
Espinel, E.
Rodriguez, J. A.
Curull, V.
Madrenas, J.
Piera, L.
Article
1984-10-01T07:00:00Z
Clinical Nephrology
Clinical Nephrology
22
211
212
Immunology and Infectious Disease
This article is not available online here, but the journal in which it was published may be available in Western Libraries. Please use the Shared Library Catalogue's <a href="http://alpha.lib.uwo.ca/">Advanced Search</a> to check our collections.<br>
Dr. Joaquin Madrenas is currently a faculty member at The University of Western Ontario.
https://ir.lib.uwo.ca/immunologypub/73
oai:ir.lib.uwo.ca:immunologypub-1087
2010-01-25T00:16:17Z
publication:mnipub
publication:immunologypub
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publication:medpub
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publication:mni
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publication:institutes
Non Immunological Analytic Data for the Differential Diagnosis between Miliary Tuberculosis (MTBC) and Bird Breeder's Disease (BBD)
Madrenas, J.
Curull, V.
Barbero, L.
Vidal, R.
Morell, F.
Article
1985-07-01T07:00:00Z
Alveolitis
Extrinsic Allergic
Anemia
Bird Fancier's Lung
Blood Cell Count
Blood Proteins
Calcium
Diagnosis
Differential
Female
Hematocrit
Hemoglobins
Humans
Hypergammaglobulinemia
Male
Sodium
Tuberculosis
Miliary
Urea
Allergologia et Immunopathologia
Allergologia et Immunopathologia
13
301
304
Immunology and Infectious Disease
A group of 86 patients diagnosed as having MTBC were compared to a group of 25 patients with BBD on the basis of various blood values included in routine analysis (hemogram, leukocyte count and differential, blood electrolyte values, urea, creatinine, total proteins and proteinogram). After statistical evaluation of the results, we concluded that the finding of low values for hemoglobin, and red blood cell (RBC) count and hematocrit, alterations of leukocyte count and differential, hypoalbuminemia, and hyponatremia, in a patient with fever and a miliary chest X-ray pattern, supports the diagnosis of MTBC. On the other hand, normal values for the above parameters, together with hypergammaglobulinemia favors the diagnosis of BBD. Our data also demonstrated a 79% mortality rate in patients with MTBC and plasma urea levels of more than 55 mg/100 ml (p less than 0.001).
This article is not available online here, but the journal in which it was published may be available in Western Libraries. Please use the Shared Library Catalogue's <a href="http://alpha.lib.uwo.ca/">Advanced Search</a> to check our collections.<br>
Dr. Joaquin Madrenas is currently a faculty member at The University of Western Ontario.
https://ir.lib.uwo.ca/immunologypub/74
oai:ir.lib.uwo.ca:immunologypub-1097
2010-01-25T00:25:45Z
publication:mnipub
publication:immunologypub
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The Effect of Cyclosporine on One-Centre Long-Term Multivariate Analysis of Kidney Transplants
Madrenas, J.
Newman, S.
McGregor, J. R.
Kovithavongs, T.
Lakey, W. H.
Dossetor, J. B.
Article
1988-06-01T07:00:00Z
Transplantation Proceedings
Transplantation Proceedings
20
86
91
Immunology and Infectious Disease
This article is not available online here, but the journal in which it was published may be available in Western Libraries. Please use the Shared Library Catalogue's <a href="http://alpha.lib.uwo.ca/">Advanced Search</a> to check our collections.<br>
Dr. Joaquin Madrenas is currently a faculty member at The University of Western Ontario.
https://ir.lib.uwo.ca/immunologypub/75
oai:ir.lib.uwo.ca:immunologypub-1099
2010-01-25T00:37:42Z
publication:mnipub
publication:immunologypub
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publication:medpub
publication:med
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The Mediators of Inflammation (Interleukin-1, Interferon-tau and Tumor Necrosis Factor) and Their Relevance to Rejection
Halloran, P. F.
Cockfield, S. M.
Madrenas, J.
Article
1989-01-01T08:00:00Z
Transplantation Proceedings
Transplantation Proceedings
21
26
Immunology and Infectious Disease
This article is not available online here, but the journal in which it was published may be available in Western Libraries. Please use the Shared Library Catalogue's <a href="http://alpha.lib.uwo.ca/">Advanced Search</a> to check our collections.<br>
Dr. Joaquin Madrenas is currently a faculty member at The University of Western Ontario.
https://ir.lib.uwo.ca/immunologypub/77
oai:ir.lib.uwo.ca:immunologypub-1098
2010-01-25T00:33:24Z
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publication:immunologypub
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The Molecular Immunology of Transplantation and Graft Rejection
Halloran, P. F.
Cockfield, S. M.
Madrenas, J.
Article
1989-01-01T08:00:00Z
Immunology and Allergy Clinics of North America
Immunology and Allergy Clinics of North America
9
1
Immunology and Infectious Disease
This article is not available online here, but the journal in which it was published may be available in Western Libraries. Please use the Shared Library Catalogue's <a href="http://alpha.lib.uwo.ca/">Advanced Search</a> to check our collections.<br>
Dr. Joaquin Madrenas is currently a faculty member at The University of Western Ontario.
https://ir.lib.uwo.ca/immunologypub/76
oai:ir.lib.uwo.ca:immunologypub-1101
2010-01-25T00:42:00Z
publication:mnipub
publication:immunologypub
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publication:medpub
publication:med
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Isolation of a Murine Renal Cell Population which Expresses a Truncated T Cell Receptor-alpha mRNA
Madrenas, J.
Pazderka, F.
Baergen, C.
Halloran, P. F.
Article
1991-01-01T08:00:00Z
Transplantation Proceedings
Transplantation Proceedings
23
837
Immunology and Infectious Disease
This article is not available online here, but the journal in which it was published may be available in Western Libraries. Please use the Shared Library Catalogue's <a href="http://alpha.lib.uwo.ca/">Advanced Search</a> to check our collections.<br>
Dr. Joaquin Madrenas is currently a faculty member at The University of Western Ontario.
https://ir.lib.uwo.ca/immunologypub/78
1007917/qualified-dublin-core/100//