Tolerance and autoimmunity in the eye

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DESCRIPTION (provided by applicant): Autoimmune uveitis is a sight threatening autoimmune disease affecting some 20/100,000 people per year. Like other autoimmune diseases, uveitis appears to result form the aberrant activation of T cells toward self antigen present within the eye. How the T cells become activated, and the mechanism of autoimmune tissue destruction is poorly understood. In mice, experimental autoimmune uveitis (EAU) can be induced by immunization with the retinal antigen, interphotoreceptor retinol binding protein (IRBP). This laboratory has optimized the production of human recombinant IRBP, and will use this to probe the nature of the IRBP specific T cells which mediate EAU. One of the fundamental processes in T cell activation is the interaction of the T cell with the antigen presenting cell, yet nothing is known about how this interaction affects EAU in vivo. In the first aim, the role of the antigen presenting cell in the priming and effector function of the IRBP specific T cell will be studied. This will be accomplished through in vivo modulation of APC function and adoptive transfer studies. These experiments will answer important questions regarding how the autoreactive T cell becomes activated, and the nature of the antigen presenting cell within the eye itself which is responsible for T cell effector function. While the transfer of EAU into na?ve mice with IRBP specific T cells has been demonstrated, the nature of the T cell that is capable of inducing disease is not known. In the second aim, a panel of IRBP specific T cell clones will be characterized for a variety of functional properties, as well as their ability to transfer EAU to normal mice. In the third aim, T cell receptor genes from select clones will be isolated and used to produce transgenic mice. These mice will provide a valuable new model system in which to further study the mechanism of EAU. Toward this aim, we will also further develop a transgenic model system in which ovalbumin is expressed in the retina. This will involve the production of new transgenic mice which express a form of ovalbumin which will be retained within the retina, rather than being secreted. Together, these studies will provide important new information as well as produce a new model system resulting in much greater understanding of the mechanisms of autoimmune uveitis.