Islet Cell Transplantation Alone in Patients With Type 1 Diabetes Mellitus: Steroid-Free Immunosuppression

SPECIFIC AIMS: 1. To reverse hyperglycemia and insulin dependency in patients with Type 1 Diabetes Mellitus by islet cell transplantation; 2. To eliminate the incidence of hypoglycemia coma and unawareness in patients with Type 1 Diabetes Mellitus by islet cell transplantation; 3. To assess long-term safety and function of successful islet cell transplants in patients with Type 1 Diabetes Mellitus; 4. To determine whether the natural history of the microvascular, macrovascular and neuropathic complications of Diabetes Mellitus are altered following successful transplantation of islet cells; and 5. To assess the effect of infliximab in preventing early islet destruction, and thereby eliminating the need for a second donor's islet cells. 6. To assess the effect of etanercept in preventing early islet destruction. 7. To assess the effect of exenatide to improve islet graft function and survival in subjects that have returned to using exogenous insulin. 8. To assess the ability of exenatide to improve islet survival at time of transplantation.

This Phase II trial will have 3 groups: Group A will receive islets from 2 donors and will not receive infliximab. Group B will receive, in addition to Daclizumab, Sirolimus, and Tacrolimus, a dose of infliximab and islets from a single donor, as per the Edmonton protocol. Everything else about the clinical trial will be the same for both groups. The first 4 patients will be assigned to Group A, the next 4 patients to Group B, the next 4 patients to Group A, and the next 4 patients to Group B (total =16). Patients in Group A will receive 1-2 transplants with cells from 2 donors. If the second donor pancreas is received and satisfactory at the same time as the first pancreas, one islet infusion will be used to infuse cells from both donors. If the second pancreas is not received until after the first transplantation, a second islet infusion will be done. A second course of five doses of Daclizumab will be started on the day of the second islet infusion). In order to determine if prolonged administration of etanercept, in combination with transplantation of cultured islets, will prevent TNF-α production and enhance engraftment, we have added Group C to the current protocol. Group C, in addition to Daclizumab, Sirolimus, and Tacrolimus, will receive Etanercept in the peri-transplant period and islets from one or more donors. The last 24 patients included in this Protocol will be in Group C if they are new, or in Group A and B Supplemental Infusion if they had previous transplants. Any Group A or B participants who are eligible for a supplemental infusion will receive etanercept but no infliximab.