Glomerulonephritis in man is a major cause of patient morbidity, mortality, and need for dialysis support and transplantation. Human glomerulonephritis appears in most, if not all, cases to be related to autoimmune causes. Much indirect evidence suggests that cell mediated immunity plays an important role in the development of glomerulonephritis. There are extensively studied models of experimental glomerulonephritis induced by administration of performed antibodies to constituents of the kidney, deposition of antigens followed by antibody in the kidney, or deposition of circulating performed immune complexes. Other endogenous models of systemic immune complex disease damage the kidney in its by stander role. These models do not lend themselves to the study of pathogenetic events involved with cell mediated immunity in the production of autoimmune glomerulonephritis when the kidney itself is the target. A model of proliferative experimental autoimmune glomerulonephritis has not previously been developed in an inbred mammalian species. We have utilized a novel approach to expose a nephritogenic antigen and have developed a new model of experimental autoimmune glomerulonephritis in inbred syngeneic rats. This model allows, for the first time, application of biologic tools to investigate pathogenetic mechanisms in the production of proliferative glomerulonephritis not previously available. The long term objectives of the present proposal are to continue their investigations into the mechanisms by which cell mediated immunity contributes to the pathogenesis of glomerulonephritis in this new model and to further delineate the interaction of cell mediated immunity and classic antibody mediated damage in this process.
The specific aims of the present proposal are: 1) to better characterize the development and natural course of this experimental autoimmune glomerulonephritis with time dose clinicopathologic studies; 2) to examine the role of antibody in development and assess the independent role of antibody alone and with cells in production of disease using passively transferred antibody and hybridomas; 3) to examine the role of cell mediated immunity in pathogenesis by adoptive transfer studies, induction in B cell deficient rats, and studies with antigen specific T cell clones; 4) to identify nephitogenic peptide(s) responsible for induction of experimental autoimmune glomerulonephritis, fractionate these peptide into minimal immunogenic fragments, and determine their amino acid sequence, then generate peptide and analog and examine them for production and prevention of disease. Indirect evidence strongly suggests that the antigen which causes experimental autoimmune glomerulonephritis in their animal model is the same antigen that causes Goodpastures syndrome in man. This mammalian model provides a unique format to examine pathogenetic events in autoimmune glomerulonephritis not previously available because of lack of an appropriate animal model. Information derived from this model may be directly applicable to the human disease counter part, Goodpastures syndrome, and possibly other types of glomerulonephritis.
