The current status of islet transplantation and its perspectives

Abstract

Transplantation of human pancreatic isolated islets can restore beta-cell function but it requires chronic immunosuppression. The outcome of islet transplantation mainly depends on both the quality of islet preparations, and the survival of the graft. The quality of islet preparations can be evaluated by the results of isolation, which determines the chance to achieve insulin independence. The survival of islet grafts is reflected by the amount of engrafted functional tissue that maintains metabolic control. Immunosuppressive therapy prevents the immunological rejection of grafts, but impairs their function and impedes their regenerative capacity. Therefore, the selection of high quality islet preparations and the reduction of toxic effects of immunosuppressive regimens might dramatically improve the outcomes. The application of stem cell therapy in islet transplantation may contribute to a better understanding of the mechanisms responsible for tissue homeostasis and immune tolerance. Xenogeneic islets may serve as an unlimited source if immune tolerance can be achieved. This may be a strategy to enable a substantial improvement in function while overcoming potentially deleterious risks.

Figure 1. The concept of eras in islet transplantation

In ERA I, points A and B represent apoptotic islets lost after isolation. C represents the transient islet culture to remove most of the undesired tissue, (dead cells, exocrine cells and donor leukocytes) but also to initiate immunosuppression. D represents the early post-transplant islet loss due to instant blood-mediated inflammatory reaction (IMBIR), and "portal storm". Finally, in E, islet grafts must stand between the chronic rejection/recurrence of autoimmune disease and the toxic side effects of the immunosuppressive regimen. In ERA II, maintenance of islet mass could be achieved by an efficient isolation method and substitution of immunosuppressants. In ERA III, a perfect islet isolation method should be developed and regeneration of islet grafts should be facilitated by using regenerative medicine. Therefore, one third of the islet mass in ERA I allows us to treat one diabetic patient. In this setting, a living-related islet transplantation will spread out world wide. Otherwise, one donor pancreas can be used to treat multiple patients. Ultimately, early diagnosis of type 1 diabetes onset and induction of beta-cell tolerance could allow pancreatic regeneration without pancreas or islet transplantation. "Time" for the X axis, "functional islet mass" and "intensity of inflammation" on the Y axis. Tx: transplantation. A: pancreas procurement and preservation. B: yield of isolated islets. C: early loss of the islets by innate immunity. D: engrafted islets. E: survived islets. 1: basal level of inflammation. 2: trigger of innate immunity. 3: adapted immunity. 4: graft accommodation. 5: chronic rejection (ERA I) or tolerance (EAR II and III). 6: occurrence of autoimmunity. Figure modified according to Ricordi et al. [7].