Anne Peters, MD, and Lori Laffel, MD, MPH, Editors
Jane Lee Chiang, MD, Managing Editor
Follow this link for Part 1: Beta-Cell Replacement
The importance of the immune response in islet cell transplants was made evident by the vastly improved outcomes in patients undergoing autotransplantation versus allotransplantation. In addition to the allogeneic immune response, patients with T1D also have an autoimmune destruction of their native beta-cells as the etiology of their disease. This autoimmune response needs to be suppressed if the transplanted beta-cells are to survive. In 2000, the group at the University of Alberta reported consistent insulin independence using a strategy that is now known as the Edmonton protocol.27 This protocol consisted of infusing at least 8,000-9,000 islet equivalents (IEQs) per kilogram of body weight (this usually required two to three separate infusions). A normal-size pancreas has an estimated ~1 million islets. It is thought that stable independence needs ~8,000-9,000 IEQs (essentially islets), so a 70-kg person needs ~600,000-700,000 islets, which represents an extremely good yield from a single pancreas.35 However, although more is better, islet number is not the only factor….
The Edmonton protocol also included an immunosuppressive regimen that avoided steroids and minimized calcineurin inhibitors, both toxic to beta-cells. An antibody against the interleukin-2 receptor (daclizumab) was used for induction therapy, and sirolimus and low-dose tacrolimus were used for long-term immunosuppression. Using these techniques, researchers were able to achieve insulin independence in seven patients.27,36
These results set off a new wave of interest in islet cell transplantation, and multiple other centers in the U.S. and worldwide began to perform islet transplants (Fig. 4.4).37 A 2007 report from the Collaborative Islet Transplant Registry showed that 28 centers in the U.S. were currently or had been active in islet transplantation and that 783 patients had received this treatment. In addition, ~65% of patients were able to achieve insulin independence, and 24% were still free of the need for insulin at three years time.38 This improvement in results has continued. The most recent report from the Collaborative Islet Transplant Registry (CITR; 2011) showed insulin independence rates of ~45% at three years.39
Hypoglycemic unawareness in islet transplant recipients decreased from 60% pretransplant to 4% at three years post-transplant, even in patients who returned to insulin use. One possible explanation for this result is that nearly 80% of patients did retain some graft function, as defined by the presence of C-peptide at three years, which helped control glucose regulation, even if exogenous insulin use was resumed.40,41 More recently, the National Institutes of Health (NIH) have supported an ongoing, multicenter trial of clinical islet transplantation that is designed to serve as a stepping stone for standardization of islet isolation and transplantation, and to provide data that can be used to support efforts to make islet transplantation a U.S. Food and Drug Administration (FDA)-approved procedure (see http://www.citisletstudy.org).
Adverse events were noted that related to infusion of the islets into the portal vein, such as elevation in liver enzymes, bleeding, and portal vein thrombosis, but these were well tolerated.42,43 More serious consequences included the development of neoplasms that were likely related to immunosuppression, a death from viral meningitis, and development of antidonor alloantibodies when immunosuppressive drugs were discontinued. Such sensitization was concerning because it could place patients at increased risk for rejection in the future and also limit the pool of acceptable donors for future islets or kidneys.44,45
PATIENT SELECTION FOR PANCREAS VERSUS PANCREATIC ISLET TRANSPLANTATION
Although solid organ pancreas transplantation has been the gold standard for the achievement of long-term insulin independence, recent advances in islet transplantation have made cellular transplants an increasingly attractive alternative for beta-cell replacement. In fact, some studies using more aggressive immunosuppression with lymphodepletion as induction therapy have demonstrated five-year insulin independence rates in greater than 50% of islet recipients. These results are now approximating those seen with PTA.
At this point, islet transplants remain in the domain of experimental trials and rarely are covered by insurance. Islet transplants after kidney transplants are covered by Medicare, and if they are part of an NIH-sponsored trial, islet transplants alone are also covered by Medicare. At this time, other insurance companies do not cover islet transplants. Islet transplantation, however, likely will become an FDA-approved procedure in the near future. By the time it is approved, the algorithm by which beta-cell replacement therapy is offered to a given patient will change. Until this change, any patient with T1D who is a candidate for pancreas transplantation (SPK, PAK, or PTA) and has a cardiovascular system that can tolerate whole organ pancreas transplantation should be offered that procedure. For patients with advanced cardiovascular disease or patients who do not wish to or cannot undergo an open surgical procedure, islet transplantation can be offered but only as part of an experimental trial (see citisletstudy.org, niddk.nih.gov, and clinicaltrials.gov). Until islet transplantations can be offered routinely as a covered service, the algorithm of who should be offered an islet versus pancreas transplant will depend on the state of the art of islet transplantation available at the time. Currently, patients who are highly sensitized or have high insulin requirements remain better candidates for solid organ pancreas transplants.
Pancreas transplantation is a safe and durable strategy to achieve insulin independence in patients with T1D. Long-term insulin independence can be achieved as well as stabilization of the devastating secondary complications of long-standing diabetes. Rigorous immune monitoring combined with aggressive immunosuppression have resulted in excellent outcomes, even in PTA recipients who remain at an increased risk for acute rejection. Nonetheless, the number of patients who can benefit from this procedure is limited by the surgical and cardiovascular stresses associated with solid organ pancreas transplantation. Although islet transplantation remains an experimental procedure, progress continues in long-term success utilizing aggressive immunosuppression protocols. Further improvements in islet isolation, immunosuppression, and new sources of beta-cells derived from stem cells will move islet transplantation into the realm of FDA-approved procedures within the next few years. Upon approval, the number of options available for beta-cell replacement will increase and potentially benefit more patients with T1D who currently are not candidates for beta-cell replacement via whole organ pancreas transplantation. These would include patients who are too old or have significant medical comorbidities, such as heart disease, that would put them at higher risk for perioperative complications.
Significant advances in the technology of islet isolation, as well as improvements in the ability to protect transplanted islets from both the alloimmune and autoimmune responses, have led to major improvements in long-term rates of insulin independence. The logistics of isolating sufficient islets from a limited pool of donors remains a major limiting factor for widespread application as a treatment for diabetes. Potential solutions for new sources include xenogeneic tissue, embyonic stem cells (ES) differentiated into insulin-producing cells, and induced pluripotent stem cells (iPS) cells.46,47
Although clinical trials using porcine islets likely will move forward in the near future, success will require novel immunosuppressive strategies to over-come the potent xenogeneic response. In addition, concerns persist regarding the risk of transmitting infectious diseases from one species to another. Although iPS-derived beta-cells have the promise of providing a source of human leukocyte antigen (HLA)–matched beta-cells for the diabetic patient, this technology has not evolved as far as the ES-derived beta-cell.48
The first clinical trials of ES-derived beta-cells will likely be moving forward in the near future. Several teams have produced insulin-producing beta-cells derived from human ES lines by culturing the cells with selected differentiation factors. These cells have been capable of reversing diabetes in immunodeficient mice. As these ES-derived beta-cells move closer to clinical trials, they will still require protection from both the alloimmune and autoimmune responses, as they express HLA derived from the ES cell line.49–51 Strategies that are being considered include the immunosuppressive regimens found to be effective in the human islet trials as well as use of an immunoisolation barrier.52 The latter strategy also will provide a barrier for undifferentiated cells, which could develop from the pluripotent ES cell line. Current platforms and immunosuppressive strategies that are successful for islet allotransplantation will form the basis for the first clinical trials for ES-derived beta-cells. The potential for an unlimited source of beta-cells undeniably will have a profound impact on the treatment of T1D.
1. There is a need for the identification of additional sources of beta-cells for replacement, either from donor organs, iPS cells, ES cells, or other options, with additional investigations aimed at improved isolation, purification, and differentiation processes.
2. There is a need for beta-cell replacement approaches that limit or reduce exposure to toxic immunosuppressive therapies.
3. Although many of the issues related to optimizing islet replacement therapy remain within the realm of research, there is a need to ensure rapid insurance reimbursement for effective treatments, such as islet transplantation.
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Used with permission by the American Diabetes Association. Copyright © 2013 American Diabetes Association.
Please note: We are proud to have Dr. Anne Peters as a member of our Advisory Board member for Diabetes In Control, Inc.