Rescue of a pancreatic islet graft after steroid therapy.

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