Long-Term Function (6 Years) of Islet Allografts in Type 1 Diabetes

Abstract

Eight type 1 diabetic patients, ages 29-41 years, with mean diabetes duration of 23 years (range 18-29 years) received islet transplants from 1 to 5 donors. Seven patients had stable kidney allografts 1-11 years before the islet transplant, and one patient had a simultaneous islet-kidney allograft. Patients' blood glucose control was poor as reflected by the mean +/- SD HbA1c of 9.1 +/- 1.7% before transplant. Of the first three patients, two (1 and 3) achieved insulin independence for 36 and 38 days, respectively. Two recipients rejected their islet grafts within 1 month (2 and 8) and therefore were excluded from analysis. The HbA1c and insulin requirement of the six remaining patients who had persistent islet function for more than 60 days was significantly reduced from 9.3 +/- 1.9 to 6.4 +/- 1.0% (P = 0.002) and from 0.75 +/- 0.15 to 0.35 +/- 0.12 U x kg(-1) x day(-1) (P < 0.001), respectively. The two patients with the longest graft survival (4 and 6) achieved a normalization or near-normalization of their HbA1c levels during 6 years in the absence of severe episodes of hypoglycemia. As demonstrated by a decline in C-peptide response during Sustacal challenge tests over a 6-year period, there was a diminution of islet allograft function over time, despite persistence of normal or near normal HbA1c. We concluded that transplantation of allogeneic islets with an islet mass comparable with whole or segmental pancreas transplants in type 1 diabetic patients can result in long-term islet allograft function; further, we concluded that, in conjunction with small dosages of exogenous insulin, a functioning islet allograft can result in near-normalization of blood glucose levels and significant improvement in HbA1c. The occurrence of severe hypoglycemic episodes observed for patients in the Diabetes Control and Complications Trial was not observed in recipients with functioning islet transplants, despite the continuous need for exogenous insulin therapy to sustain normal HbA1c over the 6-year follow-up. The significant improvement in metabolic control observed for the patients described in this study, and the potential to significantly decrease or halt the progression of diabetic complications, support the continued application of islet allotransplantation as a treatment modality for type 1 diabetic patients.

Pancreatic Islets Engineered with SA-FasL Protein Establish Robust Localized Tolerance by Inducing Regulatory T Cells in Mice

“…Restoration of insulin-secreting beta cell mass using allogeneic islet transplantation has been viewed as a preferred treatment modality and its efficacy in restoring physiological glycemic control has been demonstrated in clinical trials (4). However, the success of allogeneic islet transplantation is compromised by immunological rejection and secondary graft failure due to the continuous use of immunosuppressive drugs to control rejection (5). Therefore, novel approaches that specifically target and control destructive auto and alloimmune responses without continuous immunosuppression remain to be developed for the successful application of allogeneic islet transplantation in the clinic.…”

Xenogeneic islet re‐transplantation in mice triggers an accelerated, species‐specific rejection

“…Transplantation of pancreatic islets is a potential treatment for patients with insulin‐dependent (type 1) diabetes. The preliminary results of islet transplantation are encouraging and the number of insulin‐independent patients is increasing with improvements in the technique of islet isolation and with the use of new immune‐suppressive drugs 1–3 …”

Islet Transplantation a Decade Later and Strategies for Filling a Half-Full Glass

“…The stage for future successes in alloislet transplantation in patients with type 1 diabetes was set. Case reports and small patient series' revealed evidence for function of islets after transplantation and brief or partial improvement in glycemic control (6–11). One vexing variable was the irony that one of the drugs important generally for transplantation success, cyclosporine, had inhibitory effects on β-cell function (12–19).…”