PATHOGENESIS OF EXPERIMENTAL GLOMERULONEPHRITIS

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The broad objective of this proposal is the study of the mechanisms responsible for immunologic damage to the kidney. While antibody-mediated glomerular diseases have been modeled successfully in experimental animals and studied in detail, advances in our knowledge of cell-mediated injury involving foreign antigens have bee hampered substantially by the lack of suitable experimental models. Several forms of human renal diseases are believed to results from a cell-mediated immune injury, possibly-activated by foreign antigens, however, the precise mechanisms responsible for this type of damage, and conditions that could modulate the expression of such injury in the kidney are poorly understood. Recent cell culture studies have unraveled many of the critical steps required for effective antigen presentation by macrophages and other cell types. These new insights should prove useful in the design of studies aimed at demonstrating the potential capacity of intrinsic cells of selected nephron segments to become the target for sensitized T cells and to actively participate in diseases triggered by delayed type hypersensitivity reactions. A dual approach with in vivo and cell culture experiments hypersensitivity reactions. A dual approach with in vivo and cell culture experiments will be followed in these studies in an effort to corroborate a potential significance will be followed in these studies in an effort to corroborate a potential significance of in vitro observations in the pathogenesis of disease processes that befall an organ in the intact animal. Cells from the glomerulus will be isolated in pure form and in the intact animal. Cells from the glomerulus will be isolated in pure form and cultured under conditions that influence cell surface expression of the gene products of the major histocompatibility complex. Antigen uptake, processing, and presentation to purified T cells by glomerular cells will be studied following strategies designed to influence the intracellular re-routing or the lysosomal processing of antigens. Conditions for optimal antigen presentation in cultured cells will then be applied to in vivo experiments. Targeting of selected cells with antigens or haptens in the intact animal will be accomplished by chemical modification and/or by coupling of appropriately selected antigens to monoclonal antibodies of known specificity. Studies on animals actively immunized by various routes and adoptive transfer experiments with purified effectors cells or T cell lines will explore the role of various types of lymphocytes in the structural and functional expression of the disease. Additional in vivo studies are aimed at evaluating potential modulating effects by selected cytokines. These studies should provide key new insights into mechanisms of cell-mediated immune injury to the kidney.