Regulation of the Ocular Immune Response by RPE.

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DESCRIPTION (provided by applicant): The long-term goal of this proposed research is to understand the pathogenesis of uveitis, a T cell-mediated autoimmune disease in the eye, using experimental autoimmune uveitis (EAU) as an experimental model. Using in vitro co-culture of uveitigeneic T cells derived from rats with uveitis (EAU) and retinal pigment epithelial (RPE), a major parenchymal cell that might be targeted by uveitogeneic T cells, we have demonstrated that normal RPE cells are capable of inhibiting uveitogeneic T cell functions including proliferation and cytokine production, as evidenced by that T cells are rendered hypo-responsive to their specific antigens presented by APCs when they are pre-exposed to RPE. On the other hand, activated RPE is capable of promoting T cell responses by expression of MHC molecules and production of cytokines upon confronting uveitogenic T cells. The reciprocal interaction of uveitogeneic T cell and activated RPE elicit significant amounts of inflammatory mediators such as TNF-a, IFN-r and NO, which may increase target tissue damage. The underlying hypothesis of this project is that the outcome of interactions between uveitogenic T cells and the RPE play a critic role in the pathogenesis of the disease. Experiments are designed to determine whether uveitogenic T cells have an increased ability, compared to their nonpathogenic counterparts, to escape the suppression mediated by RPE, or they are more resistant to the apoptotic cell death induced by RPE (Specific Aim 1). We will also test an alternative possibility that uveitogenic T cells are more capable of inducing cascading responses upon interacting with RPEs. Uveitogenic T cells may induce increased expression of MHC class II or co-stimulatory molecules on RPE cells, which in turn, activate the T cells and result in excessive production of inflammatory cytokines and chemokines (Specific Aim 2). The expertise of this laboratory in generating both autoreactive T cells and RPE cells and the availability of various functional tests assessing interaction between T cells and RPE will provide a competitive advantage in the proposed studies. The results of our studies will provide new insights into the pathogenesis of uveitis.