Zhao, Zi-shan; (1995) T cell effector mechanisms in experimental autoimmune uveitis (EAU). Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Experimental autoimmune uveitis (EAU) is a T cell-mediated autoimmune model for posterior uveoretinitis in man. There is increasing evidence to suggest an important role for CD4+ T cells and their lymphokines in EAU induction, although the mechanisms involved are still not clear. Adoptive transfer of EAU in Lewis rats can be achieved using activated CD4+ T cell lines specific for retinal soluble antigen (S-Ag). However there is little information on the regulation of lymphokine expression by these uveitogenic T cell lines. In order to further understand the pathogenic mechanisms involved in EAU, S-Ag specific CD4+ T cell lines were established from Lewis rats immunized with S-Ag in CPA and were used to examine the regulation of lymphokine expression. Lymphokines present m the supernatant were assessed by bioassays and their mRNA was detected by polymerase chain reaction (PCR). All S-Ag specific cell lines established were found to be CD4+CD8-OX22low T cells. The mRNA samples were taken at 6 h and supernatant samples were taken at 24 h after stimulation. Results demonstrated that S-Ag specific T cell lines when stimulated with antigen express IL-2, IFN-γ and IL-4 mRNA. Furthermore, IL-2 and IFN-γ bioactivities correlated with gene expression of respective lymphokines except in one cell line which had no detectable IL-2. These findings suggest that the production of IL-2 and IFN-γ may play important role in EAU induction. Furthermore, the time course data (3, 6, 24, 48 and 72h) with one of S-Ag specific T cell lines showed that the proliferation of murine HT-2 cells induced by the supernatant following ConA stimulation was only partially inhibited by rat IL-2R mAb, while proliferative response induced by supernatant after S-Ag activation could be totally blocked by rat IL-2R mAb, suggesting that there are HT-2 cell growth factors other than IL-2 in the supernatants following ConA, but not S-Ag stimulation. All these suggest that the way in which the T cell is activated has an effect on its resultant lymphokine secretion. Mouse CD4+ T cell clones have been divided into Th1 and Th2 based on the patterns of lymphokines expressed, but in the rat there is still no evidence to support this. Rat CD4+ T cell clones specific for S-Ag or PPD established from antigen specific CD4+T cell lines were therefore examined for lymphokine expression. The results indicated that S-Ag specific CD4+ T cell clones exhibit mainly a Th1 pattern but also a mixed (Th0) cytokine pattern on the basis of lymphokine mRNA expression, whereas the PPD specific CD4+ T cell clones exhibit mostly a mixed (Th0) pattern but also Th1 and Th2 cytokine patterns. In the rat, CD4+ T cells could be functionally divided into OX22high and OX22low subsets based on phenotypic expression of CD45 isoforms. It has been found that lymphokine expression by OX22high and OX22high CD4+ T cells seems to correlate with that of murine CD4+ T cell clones. However, our results suggested that there is no simple correlation between rat CD4+ cell subsets (based on phenotypic expression of CD45 isoforms) and their lymphokine gene expression. Apart from inflammatory cytokines, immunosuppressive factors such as transforming growth factor-β (TGF-β) could play an important role in the down-regulation of EAU. To examine this further, the in vivo role of TGF-β1 on the course of EAU was also examined. The results showed that intraocular TGF-β1 had the effect of delaying the onset of EAU.

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