The transplantation of islets of Langerhans, procured from a deceased donor, has become a promising treatment for type 1 diabetes mellitus (T1DM). Currently, C-peptide negative patients are considered for this procedure if they display severe glycemic lability, recurrent hypoglycemic episodes, and a reduced ability to detect the symptoms of hypoglycemia. It is estimated that patients with T1DM experience 1.3 severe hypoglycemic episodes per year, with 5% of patients accounting for 54% of these episodes (Pedersen-Bjergaard et al. 2004
). It is these patients that benefit most from islet transplantation and in whom chronic immunosuppression can be justified. The indications are expanding, with microvascular and even macrovascular complications improving after transplantation (Warnock et al. 2008
; Thompson et al. 2011
In brief, islet transplantation involves the procurement of a donor pancreas with subsequent digestion and separation of the exocrine tissue and stroma from the islets. This is performed using enzyme degradation and density centrifugation. Isolated islets are assessed for quantity and quality (). Islet preparations that contain an adequate number of islets (5000 islet equivalents [IEQ] per kilogram based on recipient weight) are then transplanted into a diabetic recipient. The majority of transplants involve percutaneous cannulation of a branch of the portal vein with subsequent gravity infusion of the islet preparation (). Recipients are placed on immunosuppression and other medications designed to enhance islet engraftment and survival.
Isolated and purified human islets of Langerhans, postculture, ready for transplantation.
Portal angiogram after percutaneous transhepatic portal access, with catheter tip in the superior mesenteric vein, ready for islet infusion.
The first attempt at islet transplantation occurred in 1893 when Watson-Williams and Harsant transplanted minced sheep’s pancreas into the subcutaneous tissue of a young boy with ketoacidosis (Williams 1894
). The discovery of insulin reduced interest in transplantation as a treatment for diabetes, but was renewed in 1972 when Drs. Ballinger and Lacy demonstrated a method for isolating intact islets of Langerhans from rodents with subsequent in vivo function after transplantation in a rodent diabetes model (Ballinger and Lacy 1972
). Nearly 20 years later, Scharp et al. (1990)
achieved the first case of clinical insulin independence, which lasted nearly 1 month. This achievement was possible owing to advances in islet isolation and purification including the development of the Ricordi chamber by Dr. Camillo Ricordi in 1989
(Ricordi et al. 1989
). Further advances and experimentation culminated in the publication of the Edmonton Protocol in 2000 (Shapiro et al. 2000
). In this series of seven patients with T1DM receiving islets from multiple (2–4) donors, 100% of recipients achieved insulin independence. This study heightened the interest in islet transplantation and proposed the use of a steroid-free immunosuppression protocol, the transplantation of a larger islet mass (>11,000 IEQ/kg recipient weight) and the avoidance of islet culture before transplantation. Although islets are now routinely cultured, steroids continue to be avoided in posttransplant immunosuppression regimens. The use of multiple donors, while enabling the transplantation of a large islet mass, limits the number of patients that can receive grafts. Current data on the outcomes of islet transplantation show insulin-independence rates to be >27% at 2 yr posttransplant (Investigators 2009
). The Edmonton group and others have observed an inexorable decline in insulin independence out to 8 yr posttransplant, but with persistent C-peptide secretion and complete protection from hypoglycemic reactions in >70% of recipients (). This is through the use of multiple islet donors. Even more recent data hints at 3-yr insulin-independence rates nearing 50%.
Nine-year insulin independence and C-peptide islet graft function rates with the original Edmonton Protocol immunosuppression. (Data from the University of Alberta.)
A major international trial was initiated by the Immune Tolerance Network (ITN) both to replicate Edmonton’s success, and to set up a series of clinical sites for future trials in tolerance and islet transplantation. The major findings of that trial were that insulin independence was indeed attainable at multiple sites where a common islet isolation and clinical immunosuppressive protocol was applied, but variance in success between sites reflected site-specific experience both with the complex preparation of human islets for transplantation, and clinical experience in the routine management of immunosuppressive therapies, especially around dosing of sirolimus (SRL) (Shapiro et al. 2003
). Enabling lower islet masses from single donors to achieve insulin independence is one of the current goals in islet transplantation and would allow transplantation of a wider group of recipients and advance islet transplantation as the “treatment for all” in diabetes. In addition, the achievement of longer-term insulin independence is highly sought. Although independence out to 10 yr is possible (Berney et al. 2009
) this is certainly not standard. The focus of this work is to review the advances in islet transplantation that have made the current results possible and to look ahead at some of the future advances aimed at achieving these goals.