Objectives: To determine the impact of the Edmonton Protocol on steroid-free immunosuppression in a multicenter trial of clinical islet transplantation in brittle type 1 diabetic patients. The primary objective will be to confirm that islet allotransplantation is an appropriate model for studying tolerance strategies, thus providing a baseline patient cohort for future interventions and mechanistic studies in tolerance. The current study will define the logistic infrastructure for clinical islet transplantation across multiple centers. Standardized protocols will be defined for all aspects of islet isolation, transplantation, immunosuppression and detailed follow-up, including shipment of samples, etc.
Basis/Rationale: Clinical islet transplant recipients will prove to be key primary subjects for early evaluation of tolerance induction protocols, as graft failure (return to insulin therapy) is inconsequential compared to loss of any other solid organ transplant. Exciting preliminary data from the Edmonton Group has demonstrated 100% success in achieving sustained insulin independence in 6 patients with a median follow-up of 7.2 months using a novel steroid-free immunosuppressive regimen, representing a dramatic improvement compared with previous reports from the Islet Transplant Registry.
Significance: This multicenter study will prove that insulin independence can be achieved consistently after islet transplantation, providing a much less invasive approach to control secondary diabetic complications than whole pancreas transplantation. A large cohort of islet recipients will provide important baseline material for the tolerance assay subgroup, possibly allowing effective withdrawal of immunosuppression in selected cases, although this is not planned as part of the existing protocol. Without this important baseline trial of successful islet transplantation using an immunosuppressive approach, it will be very difficult to determine a meaningful outcome in future tolerance trials proposed as a second stage of this initiative.
Protocol Summary: A total of 9 centers in the United States, Canada and Europe will perform solitary islet transplants in 36 type 1 diabetic patients using the Edmonton protocol of anti-IL2R induction (daclizumab) with sirolimus and low dose tacrolimus steroid-free immunosuppression. Islets will be isolated and purified using standardized protocols and transplanted into the portal vein by a minimally invasive percutaneous transhepatic approach. In vitro islet viability assessment with insulin stimulation response in static glucose incubation will be completed, in addition to immunohistochemical cell composition determination. Insulin will be withdrawn early post-transplant, and metabolic function will be determined by basal and stimulated C-peptide production, and responsiveness in vivo with arginine solution.