The Roles of Costimulatory Molecules in EAAU

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DESCRIPTION (provided by applicant): Experimental autoimmune anterior uveitis (EAAU), an organ-specific autoimmune disease, has been actively investigated in recent years as an animal model of human acute anterior uveitis. In our laboratory the disease can be induced in Lewis rats by either immunization with insoluble bovine melanin-associated antigen (MAA) alone or with soluble bovine MAA with adjuvant. Since the disease can also be adoptively transferred with primed CD4+ T cells into naive Lewis rats, it is believed that EAAU is mediated by T lymphocytes. However, the mechanism by which autoimmunity to self antigen within the eye develops, and the mechanism by which it resolves, is largely unknown. Our preliminary studies demonstrate that blockade of the CD28-B7 interaction by CTLA-4-Fc can inhibit the induction and reduce the severity of EAAU. Thus, the model of EAAU in the Lewis rat provides a unique opportunity to study the role of costimulatory molecules in autoimmune diseases, including ones in an immunologically privileged site (i.e. the eye). We propose to study the following: 1) The pattern and kinetics of expression of costimulatory molecules and cytokines within the eye during natural course of EAAU; 2) The role of B7-mediated costimulation in the eye during the effector phase of EAAU; 3) The mechanism by which CTLA-4-Fc inhibits the induction of autoimmunity to MAA. Our studies should allow us to better understand the role of costimulatory molecules in response to a self-antigen. Furthermore, we will gain insight into the mechanisms involved in the regulation of costimulatory molecules, with the potential to design new selective immunotherapeutic strategies for human acute anterior uveitis.