Project: Research project

Project Details


Overall IRPG objective is to timely verify potentially breakthrough
emerging strategies based on the use of novel immunomodulatory
interventions, by multidisciplinary translational research (pre-
clinical) and pilot clinical trials to achieve our final goal of
successful islet replacement and preservation of beta cell mass in
patients with Type 1 diabetes. Current protocols of immunosuppression
impose increased metabolic demand (insulin secretion) to maintain
normoglycemia that are deleterious in a situation of reduced beta cell
mass, such as an islet cell transplant. In addition non-specific
inflammatory events and ischemia/reperfusion-like phenomena can
contribute to a significant early loss of implanted islets. Our CENTRAL
HYPOTHESIS is that islet transplants will be consistently successful in
patients receiving immunomodulatory treatments aimed at preventing early
inflammatory events while avoiding beta cell toxicity and the increased
metabolic demand imposed by conventional immunosuppression. Our pre-
clinical preliminary results indicate that recently developed non-
diabetogenic immunomodulatory strategies, based on blockade of the CD40-
CD154 T lymphocyte costimulatory pathway, promote islet engraftment and
long term function. Blockade of this early costimulatory pathway
represents a powerful treatment option for prevention of islet allograft
failures in patients with Type I diabetes, since it might allow for
prevention of rejection, autoimmunity and inflammation at the site of
islet implantation, all of which are thought to contribute to the poor
outcome of clinical islet cell transplants. Encouraging results also
suggested that donor-specific bone marrow infusion significantly improve
the outcome of solid organ grafts. Additional evidence indicates that
bone marrow transplantation might prevent onset/recurrence of
autoimmunity. It is now critical to test, in pilot clinical trials,
immunomodulatory protocols designed to maximize engraftment and survival
of islet transplants. We propose: Specific Aim number 1: To determine
whether anti-CD154 antibody (5c8) will allow islet allograft survival
in patients with Type 1 diabetes. Specific Aim number 2: To determine
whether co-transplantation of donor bone marrow cells will further
improve islet allograft survival and allow discontinuation of anti-CD154
antibody at 1 year. Specific Aim number 3: To assess the functional and
metabolic capacity of successful intrahepatic islet allografts.
Specific Aim number 4: To study the immune profile/function of patients
receiving anti-CD154 therapy and/or donor bone marrow infusion.
Effective start/end date9/30/989/29/02


  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Institute of Diabetes and Digestive and Kidney Diseases: $671,940.00


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