PANCREATIC TRANSPLANTATION AND DIABETES MELLITUS

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The detection of autoantibodies directed against pancreatic islets, islet cell surface antibody (ICSA) and islet cell antibody (ICA), in sera of patients with Type 1 diabetes mellitus has been difficult to standardize. In this project, we will examine whether the idiotype of selected islet cell monoclonal antibodies will prove to be helpful in the development of a standardized radioimmunoassay for islet cell autoantibodies. Isolated pancreatic islets have been shown to be highly vulnerable to immune rejection. The hypothesis has been advanced that cells which bear Class 2 MHC antigens are responsible for initiating the rejection process. Since endocrine cells do not express these determinants, it has been proposed that there are non-endocrine passenger cells within the islet carrying signals that are required for allograft rejection. Monoclonal antibodies directed against canine Class 2 MHC antigens will be used as immunoadorbtion reagents to delete these cellular elements from dispersed endocrine islet cells preparations. Following reaggragation of pancreatic endocrine cells, in tissue culture, they will be implanted under the renal capsule of pancreatectomized beagle dogs to determine whether hyperglycemia is reversed in the absence of immunosuppression therapy. Lastly, little is known about antigens on the surface of islet cells. Yet a vast array of cell surface receptors, including receptors for toxins such as alloxan and tetanus toxin; receptors for insulin secretagogues such as putative glucoreceptors; and receptors for catecholamines, cholinergic agents, and gut factors such as gastric inhibitory polypeptide; receptors for beta cytotrophic viruses; and receptors for growth factors, to mention just a few, are constituents of a highly organized membrane structure that will prove to be a rich source of differentiation antigens, perhaps similar in scope to those already identified on lymphocyte plasma membranes. Monoclonal antibodies, generated against rat, canine, and human islet cells will allow us to begin to study the organizational and functional relationships of some of these islet cell plasma membrane proteins.