Electronic Thesis and Dissertation Repository

Degree

Master of Science

Program

Pathology

Supervisor

Dr. Zhu-Xu Zhang

2nd Supervisor

Dr. Anthony Jevnikar

Joint Supervisor

Abstract

Heart transplantation is the only viable option for patients with end-stage heart failure. Despite advances in immunosuppressive therapies, the rate of transplanted graft loss remains substantial. Graft loss is primarily due to tissue damage mediated by immune responses. Cell death and organ rejection can occur as an active molecular process through apoptotic and necrotic pathways. We now recognize that cell death may also ensue through a newly described form of programmed necrotic cell death, termed necroptosis that involves receptor-interacting protein kinase (RIPK) 1/3. In this study, I aim to establish the role of RIPK3 in T cell-mediated chronic cardiac allograft rejection using the single MHC class II mismatch [C57BL/6 (H-2b; B6) or B6.129R1-RIPK3tm1Vmd (H-2b; RIPK3-/-) to B6.C-H-2Bm12 (H2-Ab1bm12; bm12)] transplantation model.

My studies show that allo-reactive CD4+ T-cells produce tumor necrosis factor α (TNF-α) and express Fas ligand (FasL). My results also show that CD4+ T-cell-mediated heart graft rejection is reduced in RIPK3 deficient donor grafts with reduced cellular infiltration and vasculopathy. TNF-α-mediated necroptosis was triggered in vitro with caspase 8 inhibition in B6 but not in RIPK3-/- endothelial cells. RIPK3-/- endothelial cells were resistant to CD4+ T-cell induced cell death via mechanisms involving granzyme B and FasL.

In conclusion, cytotoxic CD4+ T-cell-mediated endothelial cell death is dependent on TNF-α, and may be regulated by FasL and granzyme B. Loss of RIPK3 attenuates allo-immune responses, however, injury is not eliminated in a single MHC class II mismatch chronic rejection model.

Download

Share

COinS