Immunomodulatory therapy of human type 1 diabetes: lessons from the mouse

In this issue of the JCI, Ryu et al. in the laboratory of Denise Faustman (1) report very stimulating observations on their ability to modulate islet transplant rejection and endogenous β cell destruction by autoimmunity in the NOD mouse, a model of human type 1 diabetes. Here, I consider the relevance of their observations to the pathogenesis of type 1 diabetes (T1DM) in humans and, potentially, to immunomodulatory therapy for this disease. The current report describes multiple experiments in NOD diabetic mice and reaches several major conclusions that may be significant for the human disease (1). The authors found that administering CFA to diabetic NOD mice could prolong the survival of transplanted islets derived from other NOD mice but that this treatment had no such effect when the donor islets were from nondiabetic C57 mice. Hence, CFA blocked islet destruction associated with autoimmunity but not that due to graft rejection, strongly suggesting that these two forms of β cell destruction occur through different immunologic mechanisms. The authors attribute the protection afforded by CFA to stimulation of TNF-α production, since the effect could be blocked by administering a TNF-α antibody. Histologic examination of CFA-treated mice transplanted with NOD islets showed that after prolonged normoglycemia but subsequent relapse, both the endogenous pancreatic islets and the transplanted islets contained inflammatory infiltrates. There were no intact islets in the animals’ pancreata. Transplantation of islets from a mutant C57 strain that fails to express class I MHC antigens (due to a targeted deletion of the β2-microglobulin [B2m] gene) had an entirely different effect: After prolonged normoglycemia, CFA-treated mice transplanted with B2m–/– C57 islets carried no intact transplanted islets but their endogenous pancreatic islets were well formed and devoid of lymphocytes. Lymphocytes in these preparations were restricted to the circumference of the islets, a distribution sometimes described as peri-insular insulitis. To test the relative contribution of endogenous and transplanted islets to glycemic control following transplantation, the authors carried out nephrectomies or pancreatectomies and confirmed that endogenous β cells maintained normoglycemia in mice transplanted with B2m–/– C57 islets (1). In contrast, mice transplanted with NOD islets and treated with CFA depended on the transplanted islets to maintain normoglycemia. These results further support the idea that different immunologic mechanisms mediate β cell loss in transplant rejection and in T1DM autoimmunity. Crucially, these findings also suggest that normoglycemia after islet transplantation can be due to transplanted islet function or to blockade of the T1DM disease process and resumption of endogenous pancreatic islet insulin production and secretion. Another observation makes this point still more clearly: The authors find that established diabetes can be reversed by treating NOD mice with CFA and C57-derived splenocytes (1). Thus, it appears that if the T1DM disease process can be interrupted, at least early after the onset of diabetes, sufficient insulin production can be restored to reverse the animal’s diabetes. Whether this reversal is due to recovery of insulin secretion by β cells that were only damaged but not destroyed by the T1DM disease process or by regeneration of new β cells is unknown. Ryu et al. (1) also restored near-normal glycemia in NOD mice by implanting immunologically protected (alginate-encapsulated) C57 mouse islets intraperitoneally. They report that this pretreatment greatly increased the success of the CFA/C57 splenocyte treatment in reversing existing diabetes. Hence, it appears that normoglycemia improves β cell recovery when immunomodulatory therapy is used to block the type 1 diabetes disease process.