• Secondary end-points will include: partial graft function, as evidenced by baseline C-peptide greater than 0.5 ng/ml
  
• evidence for reduction in insulin requirements in those patients who do not achieve insulin independence
  
• improvement in metabolic control as evidenced by improvement in: HbA1C (should be < 7), mean amplitude of glycemic excursions (MAGE), mean glucose meter readings, continuous glucose monitoring, OGTT, and acute C-peptide response to arginine challenge
  
• elimination or reduction in the incidence of hypoglycemic coma or unawareness
  
• improvement in or decreased progression of microvascular, macrovascular and neuropathic complications of diabetes
  
• assessment of efficacy of infliximab in preventing early rejection - number of subjects achieving insulin independence with a single infusion
  
• assessment of efficacy of etanercept in preventing early rejection - number of subjects achieving insulin independence with a single infusion
  
• assessment of EXN to re-establish insulin independence or increase insulin secretion - reduction in insulin requirements with restoration of satisfactory glycemic control
  
• assessment of EXN to improve islet survival at time of islet transplantation - number of subjects achieving insulin independence with a single infusion
  

Procedure: Islet transplantation
Islet 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.