During the past 2 1/4 years while funded by a NIH New Investigator Research Award in Diabetes Mellitus, my laboratory has developed and initially characterized a series of anti-islet monoclonal antibodies. The antigens reacting with several of the most interesting antibodies have been defined and radioimmunoassays developed to study the binding properties of these antibodies. Through these studies we have discovered that islet cells specifically express complex """"""""neuronal"""""""" gangliosides which are receptors for monoclonal antibody A2B5 and tetanus toxin. In addition, monoclonal antibodies reacting with islet cell glycoproteins have been produced. The goal of my proposed project is to further characterize islet cell surface molecules, in particular human beta cell specific molecules, and to explore the relationship between monoclonal antibody defined cell surface molecules and the pathogenesis of Type I diabetes mellitus. Basic to the current project are monoclonal anti-islet antibodies A2B5, A1D2, B6 and the anti-tetanus toxin antibody 3D8, techniques for beta cell isolation using these antibodies, and techniques for producing human-human monoclonal anti-islet antibodies (the first of which, antibody B6, is now being characterized). Utilizing such specific antibodies in cell surface radioassays and in idiotype radioassays, I hope to detect either circulating anti-islet antibodies or islet antigens which reflect Beta cell destruction during the course of Type I diabetes mellitus in man and the BB/W diabetic rat, and if possible, define circulating lymphocytes specifically reactive with islet cell antigens. Finally, I propose to utilize these and other assays to study the effect of prednisone on the immunologic abnormalities and clinical course of early Type I diabetes. This clinical study provides us with key samples in well characterized patients. In addition, it is naturally hoped that controlled studies of immunologic intervention in early Type I diabetes similar to the published study of Elliott and coworkers will aid in finding effective therapy to prevent or limit beta cell destruction.
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