Date of Award


Degree Type


Degree Name

Doctor of Philosophy


Immunization with myelin basic protein in complete Freund's adjuvant resulted in only mild chronic-relapsing experimental allergic encephalomyelitis (EAE) with very low incidence in SJL/J mice, and no disease at all in A/J, BALB/c, C3H/HeJ, DBA/2, AKR and NZW mice. However, treatment of mice with anti-IFN{dollar}\gamma{dollar} (aIFN) monoclonal antibody (mAb) at the time of immunization determined severe disease in all those strains except AKR. Similarly, the passive induction of EAE in the SJL/J mice and in two of three resistant strains examined was significantly enhanced by aIFN mAb administration. In the SJL/J mice, administration of anti-interleukin 2 (aIL2) mAb had only a marginal effect in the active induction, but drastically reduced the manifestation of passive EAE. This was also observed even when aIL2 mAb was mixed with a disease-enhancing dose of aIFN mAb.;Kinetic studies revealed that aIFN mAb exerted its effect within 24 hr following the challenge or cell transfer. In several experiments, biotinylated aIFN (bt-aIFN) mAb was used to allow its deliberate removal by avidin. The results of these studies demonstrated that (i) the aIFN mAb exerted its effect within 24 hr after its administration, even prior to cell transfer, and (ii) given a period of 24 hr after the removal of bt-aIFN, the animals appeared to revert to the pretreatment disease susceptibility status.;The function of IFN{dollar}\gamma{dollar} and aIFN mAb in the early events of antigen-induced T cell activation was investigated in vitro. Pretreatment of murine peritoneal exudate cells (PEC) with IFN{dollar}\gamma{dollar} led to a significant increase in their ability to activate antigen (Ag) specific, short-term T cell lines. When exogenous IFN{dollar}\gamma{dollar} was added to cocultures of T cells and Ag-pulsed PEC or Ag-pulsed thymocytes or splenocytes, the T cell proliferation and interleukin 3 (IL3) production were considerably reduced. Anti-IFN{dollar}\gamma{dollar} mAb added to these cultures neutralized the inhibitory effect of the exogenous IFN{dollar}\gamma{dollar} but had no detectable effect on class II major histocompatibility gene expression by the Ag-pulsed PEC present in the same cultures. A reduction in T cell proliferation and IL3 production was also observed when the T cells were treated with IFN{dollar}\gamma{dollar} prior to coculture with the Ag-pulsed PEC. Furthermore, both the expression of IL2 receptor and calcium flux were reduced in the IFN{dollar}\gamma{dollar} treated T cell population. Determination of cell viability revealed that IFN{dollar}\gamma{dollar} rendered T cells less responsive to the Ag-pulsed PEC but did not kill them.;Inasmuch as IFN{dollar}\gamma{dollar} and interleukin 4 (IL4) antagonized each other in many aspects, the role of IL4 in EAE was also examined. The disease-enhancing effect of aIFN mAb in the active induction of EAE was clearly outweighed by anti-IL4 receptor (aIL4R) mAb administration. Both disease severity and incidence were reduced by the inclusion of aIL4R to the aIFN mAB treatment. When mouse recombinant IL4 was given under conditions that would increase its retention time and biological activities, severity and incidence of actively induced EAE were enhanced. (Abstract shortened by UMI).



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