immunotherapy for autoimmune diseases, such as uveitis, has been aimed at controlling CD4 autoreactive T cells. In this application, we propose to test a new approach, namely whether impeding the interaction between CD4 and CDS autoreactive T cells halts the progression of autoimmune uveitis. This hypothesis is supported by our findings that the adoptive transfer of in vitro activated interphotoreceptor retinoid-binding protein (IRBP)-specific T cells reproducibly induces chronic and/or recurrent uveitis in both rats and mice and that the pathogenic T cells that induce the disease contain a significant proportion of vigorously proliferating cells expressing CD8. We hypothesize that the progression of autoimmune uveitis is a consequence of the activation of increasing numbers of CDS autoreactive T cells which have a stronger tissue-damaging capability when they become highly activated, due to their greater cytotoxic activity and also because of the expression of MHC I molecules, required for T cell action, in the autoimmune organ. In this hypothesis, in the absence of CDS T cell activation, CD4 IRBP-specific T cells would induce only mild or monophasic uveitis, whereas, when CDS T cells are activated, severe recurrent uveitis would result. We will determine whether the reciprocal interaction between CD4 and CDS autoreactive T cells leads to severe tissue damage and disease progression and whether impeding this interaction blocks disease progression (Aim 1). We will also determine the factors that cause increased activation of CDS autoreactive T cells (Aim 2). Based on our preliminary results that T cells regulating autoimmune disease express high amounts of Foxp3 and that a subset of CDS IRBP-specific T cells expresses higher levels of FoxpS, we will also determine whether pathogenic CDS autoreactive T cells can be distinguished from suppressive CDS T cells by the levels of FoxpS expressed (Aim 3). Chronic and recurrent uveitis pose the highest risk for ocular complications leading to blindness in humans. To provide a working model allowing the dissection of the pathogenesis of recurrent uveitis, we have established a chronic, non-recurrent model of uveitis in the mouse and a chronic, recurrent model in the rat. Studies on the interrelationship between CD4 and CDS autoreactive T cells should provide much-needed insights into the pathogenic mechanism leading to disease progression and help in the development of supplemental therapies for this devastating disease.
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