PATHOGENESIS OF EXPERIMENTAL GLOMERULONEPHRITIS

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The goal of this research project is to analyze the mechanisms of antibody induced glomerulonephritis (GN) in rats when the target antigenic determinant is a single well-defined structure, by using monoclonal (hybridoma) antibodies as specific probes. We will produce mouse hybridomas against rat glomerular basement membrane (GBM) proteins and cultured glomerular cells, and initially define the properties of the resultant monoclonal antibodies (class and subclass of immunoglobulin, ability to fix complement and fine specificity). Different monoclonal antibody preparations will be passively administered to rats to produce functional and morphologic glomerular abnormalities. Nephritogenic and non-nephritogenic antibodies will be compared with respect to quantity of binding to kidneys, turnover rates, localization of binding and ability to fix complement with a view to defining the properties of heterologous antibodies that are critical for the induction of passive GN. The target antigens for nephritogenic and non-nephritogenic antibodies will be purified from solubilized GBM preparations, using the antibodies as specific immunoabsorbents. These antigens will be characterized, and their localization in the kidneys determined by antibody binding. Finally, attempts will be made to induce an active, auto-immune form of GN by immunizing animals with purified autologous antigens, and the immune mechanisms involved in the pathogenesis of this anto-immune GN will be analyzed by in vitro tests and adoptive transfer experiments.