A central question in the understanding of autoimmune disease processes is how T cell tolerance is developed and maintained to self antigens. Tolerance to self-antigens is acquired in the thymus through a process termed negative selection, and in the allogeneic MHC or foreign antigens are expressed only in extrathymic tissues have provided considerable insight into the mechanisms of peripheral tolerance induction, but still many questions remain. We have developed a new transgenic model for tolerance in which an allogeneic mcH antigen or IFn-gamma is expressed in the lens of the eyes, an immunologically privileged site. The lens of the eye represents and excellent model for further study of peripheral tolerance for several reasons. It lacks vascularization and lymphatic drainage Thus, this site may have unique properties concerning tolerance induction. The eye is also a prominent target in several autoimmune diseases including HLA-B27 linked Reiter's syndrome. In order to study tolerance induction to antigens expressed in the lens, transgenic mice have been produced expressing MHC class I (H-2D) or interferon gamma under expression and appear to be promising models for tolerance studies. These models will be immunohistochemistry. Experiments will also determine whether the H-2D antigen expressed in the lens is associated with Beta 2-microglobulin. The inflammatory changes taking place in these mice will be carefully evaluated histologically at different ages. Experiments are also proposed to test whether these changes are immunologically mediated. For the class I transgenic mice, we will assess the degree of tolerance to the allo class I transgenic in both in vitro and in vivo systems. For the INF-gamma transgenic mice, we will determine whether specific T cell sensitization to ocular antigens is occurring and whether IFN-gamma expression in the eye modifies the immunosuppressive nature of the eye. Finally, we propose to produce a third model by expressing I-E antigens under the control of the alpha-A crystallin promoter. In these mice, clonal deletion of Vbeta17a (I-E reactive) T cells will be assessed by monoclonal antibody staining and flow cytometry. These studies will provide important new information on the mechanisms of tolerance induction to tissue restricted antigens, and provide new mouse models for autoimmune uveitis.
