Insulin-dependent diabetes mellitus (IDDM) is caused by the autoimmune destruction of pancreatic beta cells. Thus, efforts in recent years have centered on the development of approaches to slow or prevent the destruction of the endogenous beta cells, induce their de novo regeneration, or provide them from an exogenous source by transplantation. The current proposal focuses on two of these directions. The overall long- term goals of this program are 1) to understand key components in the autoimmune response to beta cells in IDDM, in order to design new therapeutic approaches for the protection and preservation of endogenous beta cells, and 2) to develop genetically-engineered beta-cell lines to replace damaged or non-functional beta cells. The two program goals are addressed by three projects. Project 1 will utilize the nonobese diabetic (NOD) mouse model of IDDM to identify the initiating beta-cell antigens recognized by cytotoxic T lymphocytes. Project 2 will utilize adenoviral immunomodulatory genes to study the effects of downregulation of class I MHC-associated antigen presentation and/or tumor necrosis factor alpha (TNFalpha)-induced apoptosis on the development of IDDM in the NOD mouse and the Lymphocytic Choriomeningitis Virus (LCMV)-induced models of IDDM. To approach the second goal of this program, project 3 will employ transgenic mouse technique to genetically modify beta cells to undergo inducible and reversible proliferation in culture and in vivo. Finally, in Project 2, the effect of expressing immunoregulatory adenoviral genes on the survival of these genetically modified beta-cells will be assessed after allograft transplantation.
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