β Cell Replacement Therapy

Abstract

β cell replacement with either pancreas or islet transplantation has progressed immensely over the last decades with current 1- and 5-year insulin independence rates of approximately 85% and 50%, respectively. Recent advances are largely attributed to improvements in immunosuppressive regimen, donor selection, and surgical technique. However, both strategies are compromised by a scarce donor source. Xenotransplantation offers a potential solution by providing a theoretically unlimited supply of islets, but clinical application has been limited by concerns for a potent immune response against xenogeneic tissue. β cell clusters derived from embryonic or induced pluripotent stem cells represent another promising unlimited source of insulin producing cells, but clinical application is pending further advances in the function of the β cell like clusters. Exciting developments and rapid progress in all areas of β cell replacement prompted a lively debate by members of the young investigator committee of the International Pancreas and Islet Transplant Association at the 15th International Pancreas and Islet Transplant Association Congress in Melbourne and at the 26th international congress of The Transplant Society in Hong Kong. This international group of young investigators debated which modality of β cell replacement would predominate the landscape in 10 years, and their arguments are summarized here.

Xenotransplantation: back to the future?

“…Indeed, the use of transgenic pigs led to comparable results in vascularized heterotopic heart xenografts . Another potential strategy, namely encapsulation of pig islets , should also benefit from further development of genetically modified pigs. Of note, islet xenotransplantation from nongenetically modified pig‐to‐human achieved islet survival but no significant clinical improvement .…”

Current state and future evolution of pancreatic islet transplantation

“…Pig insulin has shown clinical efficacy because it was the main insulin treatment for diabetes before the advent of genetic recombinant technology in the 1980s. In addition, there are several advantages, such as unlimited and on‐demand supply, and it is ethically acceptable . For the success of xenogeneic islet transplantation, control of xenogeneic immune reaction, including hyperacute rejection and the possibility of zoonotic infection of porcine endogenous retrovirus (PERV), has been regarded as obstacles to clinical development.…”

“…Clinical trials have already been conducted in Oceania and South America for intraperitoneal porcine islet transplantation using microencapsulation . The transmission of PERV has been a major safety concern; however, no transmission has been observed to date in human or NHP recipients . Recent advances in genome‐editing technology may become a major solution in the near future …”

A20 as an immune tolerance factor can determine islet transplant outcomes

“…Type 1 diabetes (T1D) is an autoimmune condition marked by loss of glycemic control caused by immune-mediated destruction of insulin producing β cells that reside within the pancreatic islets of Langerhans (1). Replacement of lost β cells by adult islet allogeneic transplantation restores glycemic control, providing fine-tuned release of insulin in response to blood glucose in real time, something not yet achievable by manual or automatic injection of insulin or its analogues (2)(3)(4). Islet transplantation reduces exogenous insulin requirements and reverses hypo-]glycemic unawareness, a life-threatening complication of T1D (3,5,6).…”

“…Islet transplantation reduces exogenous insulin requirements and reverses hypo-]glycemic unawareness, a life-threatening complication of T1D (3,5,6). Although highly successful, the need for robust suppression of host immunity to avoid rejection precludes its indication for pediatric T1D patients, restricting the broader application of islet transplantation to adults with life-threatening hypoglycemic unawareness (2,7).…”