Pancreatic islet transplantation has become an established approach to β-cell replacement therapy for the treatment of insulin-deficient diabetes. Recent progress in techniques for islet isolation, islet culture, and peritransplant management of the islet transplant recipient has resulted in substantial improvements in metabolic and safety outcomes for patients. For patients requiring total or subtotal pancreatectomy for benign disease of the pancreas, isolation of islets from the diseased pancreas with intrahepatic transplantation of autologous islets can prevent or ameliorate postsurgical diabetes, and for patients previously experiencing painful recurrent acute or chronic pancreatitis, quality of life is substantially improved. For patients with type 1 diabetes or insulin-deficient forms of pancreatogenic (type 3c) diabetes, isolation of islets from a deceased donor pancreas with intrahepatic transplantation of allogeneic islets can ameliorate problematic hypoglycemia, stabilize glycemic lability, and maintain on-target glycemic control, consequently with improved quality of life, and often without the requirement for insulin therapy. Because the metabolic benefits are dependent on the numbers of islets transplanted that survive engraftment, recipients of autoislets are limited to receive the number of islets isolated from their own pancreas, whereas recipients of alloislets may receive islets isolated from more than one donor pancreas. The development of alternative sources of islet cells for transplantation, whether from autologous, allogeneic, or xenogeneic tissues, is an active area of investigation that promises to expand access and indications for islet transplantation in the future treatment of diabetes.

Pancreatic Islet Transplantation in Humans: Recent Progress and Future Directions.

The American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) convened a writing group to develop a consensus statement on the management of type 1 diabetes in adults. The writing group has considered the rapid development of new treatments and technologies and addressed the following topics: diagnosis, aims of management, schedule of care, diabetes self-management education and support, glucose monitoring, insulin therapy, hypoglycemia, behavioral considerations, psychosocial care, diabetic ketoacidosis, pancreas and islet transplantation, adjunctive therapies, special populations, inpatient management, and future perspectives. Although we discuss the schedule for follow-up examinations and testing, we have not included the evaluation and treatment of the chronic microvascular and macrovascular complications of diabetes as these are well-reviewed and discussed elsewhere. The writing group was aware of both national and international guidance on type 1 diabetes and did not seek to replicate this but rather aimed to highlight the major areas that health care professionals should consider when managing adults with type 1 diabetes. Though evidence-based where possible, the recommendations in the report represent the consensus opinion of the authors.

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The Management of Type 1 Diabetes in Adults. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).

Advances in β-cell replacement therapy for the treatment of type 1 diabetes.

Remarkable progress has been made in islet transplantation over a span of 40 years. Once just an experimental curiosity in mice, this therapy has moved forward, and can now provide robust therapy for highly selected patients with type 1 diabetes (T1D), refractory to stabilization by other means. This progress could not have occurred without extensive dynamic international collaboration. Currently, 1,085 patients have undergone islet transplantation at 40 international sites since the Edmonton Protocol was reported in 2000 (752 allografts, 333 autografts), according to the Collaborative Islet Transplant Registry. The long-term results of islet transplantation in selected centers now match registry data of pancreas-alone transplantation, with 6 sites reporting five-year insulin independence rates ≥50%. Islet transplantation has been criticized for the use of multiple donor pancreas organs, but progress has also occurred in single-donor success, with 10 sites reporting increased single-donor engraftment. The next wave of innovative clinical trial interventions will address instant blood-mediated inflammatory reaction (IBMIR), apoptosis, and inflammation, and will translate into further marked improvements in single-donor success. Effective control of auto- and alloimmunity is the key to long-term islet function, and high-resolution cellular and antibody-based assays will add considerable precision to this process. Advances in immunosuppression, with new antibody-based targeting of costimulatory blockade and other T-B cellular signaling, will have further profound impact on the safety record of immunotherapy. Clinical trials will move forward shortly to test out new human stem cell derived islets, and in parallel trials will move forward, testing pig islets for compatibility in patients. Induction of immunological tolerance to self-islet antigens and to allografts is a difficult challenge, but potentially within our grasp.

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Islet transplantation in type 1 diabetes: ongoing challenges, refined procedures, and long-term outcome.

Summary These preliminary data from an ongoing first-in-human phase 1/2, open-label study provide proof-of-concept that pluripotent stem cell-derived pancreatic endoderm cells (PEC-01) engrafted in type 1 diabetes patients become islet cells releasing insulin in a physiologically regulated fashion. In this study of 17 subjects aged 22-57 with type 1 diabetes, PEC-01 cells were implanted subcutaneously in VC-02 macroencapsulation devices, allowing for direct vascularization of the cells. Engraftment and insulin expression were observed in 63% of VC-02 units explanted from subjects at 3–12 months post-implant. Six of 17 subjects (35.3%) demonstrated positive C-peptide as early as 6 months post-implant. Most reported adverse events were related to surgical implant or explant procedures (27.9%) or to side-effects of immunosuppression (33.7%). Initial data suggest that pluripotent stem cells, which can be propagated to the desired biomass and differentiated into pancreatic islet-like tissue, may offer a scalable, renewable alternative to pancreatic islet transplants.

Insulin expression and C-peptide in type 1 diabetes subjects implanted with stem cell-derived pancreatic endoderm cells in an encapsulation device

Islet transplantation versus insulin therapy in patients with type 1 diabetes with severe hypoglycaemia or poorly controlled glycaemia after kidney transplantation (TRIMECO): a multicentre, randomised controlled trial

Studies of Circulating Microparticle Release in Peripheral Blood After Pancreatic Islet Transplantation

Allogeneic islet transplantation can restore insulin secretion in patients suffering from type 1 diabetes. However, the majority of islet transplant recipients experience a gradual decline in graft function (1). Several studies have implicated immune rejection in the loss of grafted islets (2, 3). Recently, our group reported a decline in islet graft function in association with human leukocyte antigen (HLA) sensitization in an islet transplant recipient and the recovery of islet function after treatment with an anti-CD20 monoclonal antibody (4). In this report, we document the decline of islet function in an islet transplant recipient and the recovery of the graft after steroid bolus therapy. The patient was a 43-year-old woman with a 37-year history of diabetes who underwent islet transplantation because of metabolic instability as part of a clinical trial (GRAGIL-TRIMECO). Tests for HLA antibodies using the Luminex technique were consistently negative for HLA classes I and II. The patient received a graft containing 7400 islet equivalents per kilogram body weight from a single donor by percutaneous intraportal infusion. A pretransplant complement-dependent Tand B-cell cross-match was negative. Immunosuppression was achieved by treating the patient with tacrolimus (Prograf; Fujisawa, Osaka, Japan; 2 mg/day), mycophenolate mofetil(CellCept;Roche,Basel,Switzerland; 2 g/day), antithymocyte globulin (Thymoglobulin; Genzyme SAS, Saint-Germain-enLaye, France; total dose of 6 mg/kg), and etanercept (Enbrel; Pfizer, Groton, CT; 50 mg intravenously at day 0, then 25 mg subcutaneously on days 3, 5, and 10) induction. Immediately after islet transplantation, fasting C-peptide levels increased from 0 to 1.2 ng/mL (normal range: 0.8–3 ng/mL). The patient was treated by subcutaneous insulin infusionwithexternalpump,andtheinsulin requirementsdecreasedslowlyfrom26to17 IU/day. One month after transplantation, a postprandial glucose peak greater than 11 mmol/L was observed, with C-peptide levels decreasing to 0.3 ng/mL and an increase in insulin requirements to 30 IU/day. Treatment with steroid boluses (methylprednisolone; Pfizer; 10 mg/kg for 3 days and then 6, 4 and 2 mg/kg for 1 day) was initiated 4 days after the decrease in Cpeptide. Continuous intravenous insulin therapy (Umuline Rapide; Eli Lilly, Indianapolis, IN; 3– 4.5 IU/hr) was administered to prevent hyperglycemia during the steroid therapy. Four days after steroid therapy, C-peptide levels were restored to 1.3 ng/mL, with insulin requirements under external pump slowly decreasing from 35 to 15 IU/day (Fig. 1). In the absence of an identified cause of islet loss, a diagnosis of acute cellular islet rejection was proposed. An assay for anti-HLA antibodies using the Luminex technique remained consistently negative for HLA classes I and II. In addition, cross-matches performed with sera collected at the time of the graft dysfunction episode remained negative. No islet autoantibodies against glutamate acid decarboxylase 65 (GAD65) or IA-2 were detected. Tacrolimus trough levels were 11.5 g/L. There was no clinical or biological sign of infection. Polymerase chain reaction using primers specific for cytomegalovirus and Epstein-Barr virus yielded no detectable product. At 3 months after the first islet injection, the patient received a second islet graft of 6545 islet equivalents per kilogram body weight with basilixumab (Simulect, Novartis, Basel, Switzerland; 20 mg intravenously at days 0 and 4) and etanercept (Enbrel; Pfizer) in induction. One month later, the patient was insulin-free and has remained so for 8 months. 1,8 8

Harald Egelhofer

Papers

Islet transplantation versus insulin therapy in patients with type 1 diabetes with severe hypoglycaemia or poorly controlled glycaemia after kidney transplantation (TRIMECO): a multicentre, randomised controlled trial

Studies of Circulating Microparticle Release in Peripheral Blood After Pancreatic Islet Transplantation

Rescue of a pancreatic islet graft after steroid therapy.