This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Objectives: To determine the impact of the Edmonton protocol of steriod-free immunosuppression in a multi-center trial of clinical islet transplantation in type 1 diabetic patients. The primary objective will be to confirm that islet allotransplantion 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, defined interaction with reference laboratories including the tolerance assay subgroup and other core facilities, and development of a common database for statistical analysis (EMMES Corporation).Basis/Rationale: Clinical islet transplant recipients will prove to be key primary subjects for early evaluation of tolerance induction protocols in the Immune Tolerance Network, since graft failure (return to insulin therapy) is inconsequential compared to the loss of any other solid organ transplant. Existing preliminary data from the Edmonton group has demonstrated 100% success in achieving sustained insulin independence in 12 patients with a follow-up from 1 to 18 months using a novel steriod-free immunosuppressive regimen, representing dramatic improvement compared with previous reports from the Islet Transplant Registry. The degree of success by other centers in reproducing this protocol and results will determine which centers may participate in future tolerance strategies. Significance and Relevance to Immune Tolerance: This multicenter study will prove that insulin independence can be achieved consistently after islet transplantation, providing a much less invasive approach in control of secondary diabetic complications than whole pancreas transplantation. The large cohort of islet recipients will provide important baseline material for the tolerance assay subgroup, possibly allowing effective withdrawal of immunosuppression in selected cases. 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 10 centers in the United States, Canada and Europe will perform solitary islet transplants in 40 type 1 diabetic patients using the Edmonton protocol of anti-IL-2R receptor antibody therapy induction immunuosuppression (daclizumab) with sirolimus and low-dose tacrolimus steroid-free maintenance 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 in a single reference laboratory. Islets will be transplanted sequentially from two donor organs at least one week, but less than 3 months apart. Insulin will be withdrawn after the second transplant, and metabolic function will be determined by basal and arginine-stimulated C-peptide levels.Role of GCRC: The GCRC will be asked to provide the structure necessary to conduct this clinical research trial. We will use both the in and outpatient beds in carrying out this protocol. Patients will be admitted to the GCRC the day of the islet cell transplant (day 0) to begin the immunotherapy required for this protocol. They will remain as inpatients on the GCRC for 1 day post transplant for post islet transplant recovery, monitoring and continuation of immunotherapy. Patients will be discharged on the second day (day 2). Patients will return to the GCRC as outpatients for 18 post transplant follow-up visits. The GCRC nursing staff is needed to provide the careful monitoring necessary to maintain blood glucoses in the normoglycemic range pre and post transplant. Nursing expertise will also be relied upon for precise collection of specimens and careful monitoring of patients after their islet transplant procedure and following administration of immunotherapy.
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