The experiments outlined in this proposal are aimed at the development of murine models for the investigation of mechanisms involved in the immunopathologic phenomena associated with certain poorly understood ocular inflammatory diseases, including uveitis, scleritis, and Sjogren's syndrome. In order to elucidate the immunopathogenetic mechanisms involved, a series of investigations are proposed utilizing inbred autoimmune strains of mice, primarily the MRL/Mp strain. The MRL/Mp mouse is prone to autoimmune disease and exists in two substrains, the MRL/Mp-+/+ and the MRL/Mp-lpr/lpr mouse. The lpr gene is a single autosomal mutation which induces massive lymphoproliferation of T cells and markedly accelerates the course of the autoimmune disease. Both substrains develop lacrimal gland inflammation, and aged MRL/Mp-lpr/lrp mice develop choroiditis and scleritis. Studies in this animal system will: 1) characterize the temporal evolution of the inflammatory infiltrate; 2) characterize immunohistologically the mononuclear cell infiltrate in the target ocular tissues, utilizing monoclonal antibodies to cell surface antigens; and 3) investigate the mechanisms by which tissue destruction occurs in the target ocular tissues. Attempts will also be made to directly induce site-specific ocular lesions within these mice utilizing 1) the type II collagen arthritis model for production of murine scleritis and 2) induction of experimental allergic uveoretinitis (EAU) by immunization with retinal S antigen. A further phase of these investigations will be directed toward alteration of naturally occurring or induced immunopathology by treatment of the MRL/Mp mouse with the immunomodulating agent cyclosporine.
