Clinical islet transplant: current and future directions towards tolerance

Abstract

The ultimate goal of islet transplantation is to completely correct the diabetic state from an unlimited donor source, without the need for chronic immunosuppressive drug therapy. Although islet transplantation provides an opportunity to develop innovative strategies for tolerance in the clinic, both alloimmune and autoimmune barriers must be controlled, if stable graft function is to be maintained long-term. After islet extraction from the pancreas, the cellular graft may be stored in tissue culture or cryopreserved for banking, providing an opportunity not only to optimally condition the recipient but also to allow in vitro immunologic manipulation of the graft before transplantation, unlike solid organ grafts. As such, islets may be considered a "special case." Remarkable progress has occurred in the last three years, with dramatic improvements in outcomes after clinical islet transplantation. The introduction of a steroid-free, sirolimus-based, anti-rejection protocol and islets prepared from two (or rarely three) donors led to high rates of insulin independence. The "Edmonton Protocol" has been successfully replicated by other centers in an international multicenter trial. A number of key refinements in pancreas transportation, processing, purification on non-ficoll-based media, storage of islets in culture for two days and newer immunological conditioning and induction therapies have led to continued advancement through extensive collaboration between key centers. This review outlines the historical development of islet transplantation over the past 30 years, provides an update on current clinical outcomes, and summarizes a series of unique opportunities for development and early testing of tolerance protocols in patients.

Alleviation of hyperglycemia in diabetic rats by intraportal injection of insulin-producing cells generated from surgically resected human pancreatic tissue

“…However, the paucity of donor pancreases and problematic harvest of sufficient islet cells from cadaverous donors remain the drawbacks to this therapeutic strategy. In previous studies, multiple donors as well as transplantations were required to achieve insulin independence, with a 1-year insulinindependent rate of 44% and only a 10% insulin-independent rate after a 5-year follow-up (Shapiro et al 2003. Therefore, identification of new cell sources is necessary to develop future replacement strategies.…”

Islet transplantation outcomes in mice are better with fresh islets and exendin-4 treatment

“…The Edmonton protocol used freshly isolated islets rather than cultured, although it was unclear how much of an effect this contributed to the favourable outcome of the transplants [2]. Since then, the Edmonton group and others have reverted to transplanting cultured islets [9][10][11]. It is therefore of interest to investigate whether there is indeed any advantage in transplanting freshly isolated islets.…”

Beta Cell Replacement Therapy

“…The alloimmune response is primarily directed against mismatched HLA. The autoimmune response which already exists in type 1 diabetic recipients, being the source of the pathogenesis of the disease and is specifically reactive to beta cell markers such as glutamic acid decarboxylase (GAD65) and islet cell antigen (ICA) (Shapiro et al, 2003). Immunosuppressive regimens for islet cell transplant recipients must counter these aspects of the whole immune response for improved graft survival.…”