Grant: Operating Grant

Type 1 diabetes is an autoimmune disease in which the cells of the pancreas that secrete insulin, called beta cells, are destroyed by the patient's own immune system. Despite decades of research, we are still not able to prevent or reverse this disease process in humans. We believe the best chance for a cure is to restore functional beta cells by either activating regeneration of these cells in the pancreas, or by replacing them through transplantation. Our goal with this proposal is to assess a novel compound that we believe could be used to treat type 1 diabetes. In previous research, we determined that a naturally occurring protein called B7-H4 can selectively suppress the immune cells that are responsible for killing insulin-secreting beta cells and thereby reduce the incidence of diabetes in mice. Our studies also suggest that increasing the amount of B7-H4 protein within pancreatic cells (through genetic engineering) prior to transplantation may inhibit the recurrence of diabetes in mice receiving the transplanted cells. We therefore aim to determine: (1) Can B7-H4 protein influence the development of diabetes in mouse models of the disease, if we: (a) inject B7-H4 protein directly into the mice; (b) increase the amount of B7-H4 protein in islet beta cells by genetic engineering; or (c) induce B7-H4 deficiency through genetic engineering? (2) If B7-H4 does prevent diabetes, then through what mechanism(s)? We will determine: (a) the effect of B7-H4 protein on the response, function, amount and balance of the various immune cells that either protect or destroy beta cells, and (b) the level of B7-H4 protein in beta cells required to protect beta cells from death. The use of B7-H4 protein may help to prevent and reverse the development of T1D and provide a more natural compound to treat the underlying autoimmune disease process.