The migration of pathogenic T cells to the pancreas, and their subsequent activation and proliferation, are important steps in the pathogenesis of type I diabetes. CD98 is a heterodimeric transmembrane protein that functions in amino acid transport and integrin signaling. Integrin expression and function are important for autoimmune diabetes in the NOD mouse model, and proliferation of T cells in pancreatic draining lymph nodes is a hallmark of disease. Therefore we have begun investigating CD98 as a potential target in type I diabetes. Our preliminary data shows that T cells in which CD98 has been targeted are unable to transfer disease, while transfer of control T cells causes beta cell destruction and overt diabetes. Our overall hypothesis is that CD98 controls migration or proliferation of diabetogenic T cells, and thus is a potential target for disease intervention. The research proposed in this application will Investigate the cellular and biochemical mechanisms by which CD98 deletion protects from type I diabetes, and to study potential side effects of CD98 targeting on normal immune responses.
Blocking the autoimmune attack mediated by lymphocytes in type I diabetes is a high priority, both to prevent the disease, and to stop its recurrence after islet cell transplant. We found that deleting CD98 on T lymphocyte immune cells makes them unable to cause experimental type I diabetes. We are proposing to investigate the mechanism of this protection, and to test what CD98 targeting might do to normal immune responses.
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