No abstract

Porcine islet transplantation is an alternative to allo-islet transplantation.Retransplantation of islets is a routine clinical practice in islet allotransplantation in immunosuppressed recipients and will most likely be required in islet xenotransplantation in immunosuppressed recipients. We examined whether a second infusion of porcine islets could restore normoglycemia and further evaluated the efficacy of a clinically available immunosuppression regimen including anti-thymocyte globulin for induction; belimumab, sirolimus, and tofacitinib for maintenance and adalimumab, anakinra, IVIg, and tocilizumab for inflammation control in a pig to nonhuman primate transplantation setting. Of note, all nonhuman primates were normoglycemic after the retransplantation of porcine islets without induction therapy. Graft survival was >100 days for all 3 recipients, and 1 of the 3 monkeys showed insulin independence for >237 days. Serious lymphodepletion was not observed, and rhesus cytomegalovirus reactivation was controlled without any serious adverse effects throughout the observation period in all recipients. These results support the clinical applicability of additional infusions of porcine islets. The maintenance immunosuppression regimen we used could protect the reinfused islets from acute rejection.

High mobility group box 1 (HMGB1) is an infamous alarmin which is known to be harmful to pancreatic beta cells and associated with diabetes mellitus pathogenesis and pancreatic islet graft failure. However, recent studies have indicated that cytosolic HMGB1 could function as a modulator to relieve cells from apoptotic stress by inducing autophagy. Particularly, pancreatic beta cells have been well-known to demonstrate the apoptosis to autophagy switch when exposed to hypoxia or lipoxiticy. In this study, we have investigated the beta cells under hypoxic and lipotoxic stress with CCK8 assay and flow cytometry while utilizing a small molecule inhibitor of HMGB1 which can suppress the cytosolic accumulation of HMGB1. The results demonstrated that the cytoplasmic HMGB1 blockade decreased the viability of mouse beta cell line MIN6 and primary islets. Moreover, the cytoplasmic HMGB1 blockade decreased the autophagic flux and increased the ratio of apoptotic MIN6 cells. Also, it was noteworthy that the MIN6 cells have shown high autophagic flux even in basal state. We believe this study linked the role of cytoplasmic HMGB1 in apoptosis to autophagy switch and the importance of autophagy in beta cells under apoptotic stress. We expect this study to open up a novel field of HMGB1 utilization within diabetes- and islet transplantation-related therapeutics, where the current field is mainly focused on the exhaustive blockade of HMGB1.