EXCEED THE SPACE PROVIDED. Transplantation tolerance induction based on blockade of co-stimulation greatly prolongs islet and skin allograft sur- vival in rodents and primates. We now propose to translate these basic research studies for use in human islet allotrans- plantation. Wehypothesize that a two-elementprotocol consisting of a single donor-specific transfusion (DST) plus a brief course ofcmti-CD154 (anti-CD40 ligand) antibody will induce permanent islet allograft survival in humans with diabetes mellitus secondary to surgical pancreatectomy. We further hypothesize that these islet allografts will survive in the absence of chronic immunosuppression. These hypotheses are based on our observation that the two-element protocol induces permanent islet allograft survival in chemically diabetic mice and long-term skin allograft survival in non-human primates (>185 days and still ongoing). We propose to initiate a clinical trial using a novel investigational anti-CD 154 monoclonal reagent, IDEC-131, being made available to our laboratory specifically for this purpose. We propose to trans- late our two-element protocol for use in treating human diabetes mellitusby intrahepatic islet transplantation. Specific Aim 1 is to perform curative islet allotransplantation in patients with "secondary" insulin-requiring diabetes due to total or sub-total pancreatectomy. This form of diabetes is typically difficult to control and associated with signifi- cant morbidity. In addition, it occurs in the absence of autoimmunity and insulin resistance, two factors that could confound the outcome of a phase II translational clinical trial. Treatment of the secondary insulin-requiring diabetes that occurs after total or partial pancreatectomy by insulin injection is not curative; transplantation offers the only contemporary hope of a cure. Cure of diabetes without recourse to chronic immunosuppression[unreadable]which in any event is largely ineffective for islet allografts[unreadable]is arguably the Holy Grail of diabetologists Specific Aim 2 to initiate an investigation of the mechanism(s) by which allograft tolerance is induced in islet allograft recipients and to assess a novel cytokine analysis using peripheral blood lymphocytes that will permit us to anticipate episodes of allograft rejection. These studies will be undertaken in collaboration with investigators at Harvard and Cornell Medical Schools. It is our hope that this trial may open the way to a new approach to allotransplantation in general.