Abstract
Islet transplantation is the most valid approach to the treatment of type 1 diabetes. However, the function of transplanted islets is often compromised since a large number of β cells undergo apoptosis induced by stress and the immune rejection response elicited by the recipient after transplantation. Conventional treatment for islet transplantation is to administer immunosuppressive drugs to the recipient to suppress the immune rejection response mounted against transplanted islets. Induction of protective genes in the recipient (e.g., heme oxygenase-1 (HO-1), A20/tumor necrosis factor alpha inducible protein3 (tnfaip3), biliverdin reductase (BVR), Bcl2, and others) or administration of one or more of the products of HO-1 to the donor, the islets themselves, and/or the recipient offers an alternative or synergistic approach to improve islet graft survival and function. In this perspective, we summarize studies describing the protective effects of these genes on islet survival and function in rodent allogeneic and xenogeneic transplantation models and the prevention of onset of diabetes, with emphasis on HO-1, A20, and BVR. Such approaches are also appealing to islet autotransplantation in patients with chronic pancreatitis after total pancreatectomy, a procedure that currently only leads to 1/3 of transplanted patients being diabetes-free.
Highlights
Type 1 diabetes (T1D) is caused by the death of insulinproducing pancreatic β cells within the pancreas
The effectiveness of autologous islet transplantation, a procedure currently implemented in the clinic to treat patients suffering from chronic pancreatitis, is impacted by β cell apoptosis posttransplantation, that is, only 1/3 of the patients are insulin-free after total pancreatectomy and islet autotransplantation [8,9,10]
Donor islet quality plays a critical role in determining the outcome of allo- and autotransplantation of islet grafts, with stress-induced β cell apoptosis greatly contributing to failure of these procedures
Summary
Type 1 diabetes (T1D) is caused by the death of insulinproducing pancreatic β cells within the pancreas. At least 2-3 donors are needed per recipient to ensure survival of a sufficient islet cell mass to achieve insulin independence [3,4,5,6] Those islets that survive need to sustain an allograft rejection response and recurrence of autoimmunity mediated by the recipients’ T cells, natural killer cells, monocytes, and cytokines, otherwise additional islet/β cell death would ensue [7]. Both obstacles have significantly limited clinical application of islet transplantation for the treatment of T1D. There is evidence that each product of HO-1, biliverdin/bilirubin, CO, or ferritin accounts for its protective effects both when used alone or in combination [29,30,31,32]
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