Initially funded by a New Investigator award in Diabetes Mellitus and then the current RO1 my laboratory has developed and characterized a series of monoclonal anti-islet antibodies, discovered that islets express complex glycolipids (ganglioside receptors for monoclonals, A2B5, 3G5, and tetanus toxin), provided evidence that a major subset of patients anti-islet autoantibodies react with similar glycolipids, discovered a series of islet glycoprotein antigens (p120 """"""""calcium modulator"""""""", monoclonals 4F2 and LC7/2; p67, monoclonal HISL-19; p100, monoclonals HISL-5, 9 and 14; p24 monoclonal AID2), assessed physiologic effects of monoclonal antibody binding to the surface of neurendocrine cells, developed a clinical double immunoflourescent anti-islet antibody assay utilizing rhodaminated monoclonal BISL-32, described the T lymphopenia of the BB rat and its relation to diabetes in breeding studies, described Ia positive T cells associated with Type I diabetes, discovered the 3G5 T cell subset which increases linearly with age in man, and characterized immunologic and metabolic assays which on a research basis allow us to predict the development and approximate time of onset of Type I diabetes. A balance of immune destruction and beta cell regeneration may determine the rate at which Type I diabetes develops in the BB rat, NOD mouse and man. With the above background information, reagents, and prospective clinical studies, major goals of the current project include; 1) biochemical characterization of the islet complex glycolipids which are receptors for monoclonal antibodies A2B5, 3G5 and patients autoantibodies. 2) development of quantitative assays for autoantibodies reacting with these glycolipids, and 3) pilot studies of cell mediated immune responses to purified glycolipids and linkage in the NOD mouse of glycolipid polymorphisms to diabetogenic genes. In addition we propose to utilize our current series of monoclonal anti-islet antibodies and new monoclonals specifically produced to regenerating rat islets to study islet cell growth. In our partial pancreatectomy model of islet regeneration we propose to study; 1) monoclonal antibody defined islet differentiation antigens, 2) islet """"""""microenvironment"""""""" antigens (e.g., Factor VIII, MHC class I and class II antigens), 3) islet """"""""activation"""""""" antigens, and 4) the ability of specific monoclonal antibodies to stimulate islet cell growth.
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