The role of Ia-positive (Ia+) cells in the pathogenesis of autoimmune diseases mediated by CD4+ T cells is uncertain. Ia+ cells are of two types, bone-marrow derived and non-bone-marrow derived. Ia expression is often dependent on induction by IFN-gamma. The functions of Ia+ antigen-presenting cells (APC) include; processing, presentation, and costimulation, the provision of signal(s) required to fully activate antigen-specific, CD4+ Th1 cells, leading to IL-2 production and proliferation. Costimulatory potential appears to be a property of bone- marrow derived cells and may distinguish between """"""""professional"""""""" APC'S, i.e. bone-marrow (BM) derived cells such as macrophages or activated B cells; and """"""""non-professional"""""""" APC's, i.e. non-BM-derived cells with inducible Ia such as glia or vascular endothelium. Recent results suggest that interaction of T cells with antigen in the context of Ia on cells lacking costimulatory ability leads to induction of """"""""anergy"""""""" in T cells; i.e. long-term, antigen-specific unresponsiveness. We wish to determine: 1.) if the presence of BM-derived APC in the retina is required for the manifestation of retinal S-antigen-mediated experimental autoimmune uveoretinitis (EAU); and 2). if non-BM-derived, Ia+ cells regulate the response. The non-BM derived cells might mediate inhibition by their inability to provide costimulation, thus engaging those T cells in abortive activation programs or anergy. Alternatively, non-BM-derived Ia+ cells might be involved in initiation and amplification of the inflammation. We propose to use rat radiation/BM chimeras in conjunction with adoptive transfer of antigen-specific, pathogenic T cell lines. Further studies will be done using nude mice grafted with rat fetal thymus. These mice develop spontaneous autoimmune uveoretinitis and provide a complementary system for study of the mechanisms of peripheral antigen-presentation in that their lymphocytes are presumed to be positively selected on rat epithelium and hence rat MHC restricted. Nevertheless, the animals are immunocompetent, demonstrating antigen presentation by murine APC's in the periphery. Characterization of the disease process, especially the APC'S, is planned. The spontaneous occurrence of disease also allows a unique approach to study the mechanisms in pathogenesis.
