Importance of hyperglycemia on the primary function of allogeneic islet transplants1

Background. Hyperglycemia has been shown to influence primary function of islet isografts. In this study, we investigated the influence of hyperglycemia on primary function of allogeneic islets transplanted into spontaneously diabetic recipients (NOD) or streptozotocin-induced diabetic mice (BALB/c). Methods. Mice with moderate, severe, or very severe hyperglycemia underwent transplantation with a marginal number of islets (350 into BALB/c mice and 700 into NOD mice). To prevent the alloimmune response, we used blockade of CD28:B7 and CD40L:CD40 costimulatory signaling pathways to determine the effect of hyperglycemia alone. Blood glucose levels of the mice were monitored after transplantation, and the grafts were assessed morphologically. Results. Transplantation of allogeneic islets into moderately hyperglycemic BALB/c mice or severely diabetic NOD mice normalized the blood glucose levels in all mice within 3 days after transplantation, demonstrating the primary function of the graft. However, primary nonfunction was observed in all animals when islet transplantation was performed into severely diabetic BALB/c mice or very severely diabetic NOD mice. When mice were treated with costimulation blockade, reversal of diabetes was observed in severely diabetic BALB/c mice 15 days after transplantation, showing that the islets could adapt to the environment and function. However, transplantation of islets into NOD mice with very severe diabetes treated with costimulation blockade did not reverse diabetes, showing that even in the absence of alloimmune responses and given an adaptation period, the islets could not function. Conclusions. This study demonstrates that severe hyperglycemia impairs islet allograft function in BALB/c and NOD mice and that successful islet allotransplantation depends on the degree of hyperglycemia in the recipient.