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Allogeneic pancreatic islet transplantation has the potential to cure type 1 diabetes. One of the barriers to islet transplantation is the alloreactive T-cell response between donors and recipients. Costimulatory molecules, which play a major role in the regulation of the immune response to antigens during graft rejection, may be used to inhibit allograft destruction. B7-H4 is one such member in the costimulatory family, which has established negative regulatory function of T-cell responses.To determine whether local expression of B7-H4 protein can protect β cells from damage in islet allotransplantation, we have constructed a recombinant adenovirus expressing a B7-H4 complementary deoxyribonucleic acid (Ad-B7-H4). To study the in vivo effects of B7-H4 expression on islet graft survival, adenovirus-transduced islets from donor Balb/c mice were transplanted into streptozotocin-diabetic C57BL/6 mice (n=12).Expression of B7-H4 in islets by Ad-B7-H4 transduction at an optimized condition did not inhibit glucose-stimulated insulin secretion of the treated islets. The recipient mice transplanted with Ad-B7-H4–transduced islets established euglycemia for a longer time (mean 56.5 days), compared with control mice transplanted with Ad-LacZ–transduced islets (mean 14.5 days, [n=12, P<0.001]). Splenocytes isolated from the recipients of Ad-B7-H4–transduced islets showed hyporesponsiveness to alloantigenic stimulation, compared with control recipients. CD45 and insulin staining of the graft transplanted with Ad-B7-H4–transduced islets indicated the preservation of β cells and decrease of infiltrating immune cells.Local expression of B7-H4 prolongs islet allograft survival in vivo, suggesting translational potential for β-cell replacement with reduced immune injury.