Islet transplantation-immunological challenges and current perspectives

Abstract

Pancreatic islet transplantation is a minimally invasive procedure aiming to reverse the effects of insulin deficiency in patients with type 1 diabetes (T1D) by transplanting pancreatic beta cells. Overall, pancreatic islet transplantation has improved to a great extent, and cellular replacement will likely become the mainstay treatment. We review pancreatic islet transplantation as a treatment for T1D and the immunological challenges faced. Published data demonstrated that the time for islet cell transfusion varied between 2 and 10 h. Approximately 54% of the patients gained insulin independence at the end of the first year, while only 20% remained insulin-free at the end of the second year. Eventually, most transplanted patients return to using some form of exogenous insulin within a few years after the transplantation, which imposed the need to improve immunological factors before transplantation. We also discuss the immunosuppressive regimens, apoptotic donor lymphocytes, anti-TIM-1 antibodies, mixed chimerism-based tolerance induction, induction of antigen-specific tolerance utilizing ethylene carbodiimide-fixed splenocytes, pretransplant infusions of donor apoptotic cells, B cell depletion, preconditioning of isolated islets, inducing local immunotolerance, cell encapsulation and immunoisolation, using of biomaterials, immunomodulatory cells, etc.

Keywords: Islet transplantation; Type 1 diabetes; Diabetes mellitus; Immune tolerance; Graft rejection; T regulatory cells; B regulatory cells

Core Tip: Type 1 diabetes (T1D) is associated with loss of beta-cell mass and insulin secretion. Regardless of its nature, autoimmune or idiopathic, the loss of own insulin secretion is a hallmark dysfunction in T1D mellitus; thus, therapeutic options are aimed at either replacing the missing insulin or restoring physiological insulin secretion to achieve normoglycemia and postponing micro- and macrovascular complications. Nevertheless, the need to completely replace the depleted pancreatic secretion also leads to the emergence of new therapeutic horizons, including pancreas and islet cell transplantation. However, this approach also meets several immunological challenges-cellular and antibody-mediated rejection and loss of function. To improve the outcomes, several approaches are performed: Immunosuppression, apoptotic donor lymphocytes, anti-TIM-1 antibodies, mixed chimerism-based tolerance induction, induction of antigen-specific tolerance utilizing ethylene carbodiimide-fixed splenocytes, infusion of donor apoptotic cells before transplantation, combined with anti-CD40L antibodies and rapamycin, preconditioning of isolated islets, inducing local immunotolerance, cell encapsulation and immunoisolation, using of biomaterials, immunomodulatory cells, etc. mesenchymal stem cells, as an adjunct therapy to islet transplantation, can promote long-term graft survival, possibly by reducing inflammation and enhancing immune tolerance.