PATHWAYS TO TOLERANCE IN HUMAN ISLET TRANSPLANTATION

Project: Research project

Project Details

Description

DESCRIPTION (Adapted from the Investigator's Abstract): The CENTRAL HYPOTHESIS
of this grant application is that co-stimulatory blockade will effectively
enhance human islet allograft survival in patients with Type 1 diabetes and,
when combined with additional immunomodulatory strategies, will result in donor
specific tolerance and prevention of reoccurrence of autoimmune beta cell
destruction. The proposed immunomodulatory approaches will include recipient
treatment with humanized anti-CD154, anti-B7.1/B7.2, and anti-CD45RB specific
monoclonal antibodies. Infusion of stem cell (CD34 selected) enriched
fractions, obtained from the islet donors' vertebral bodies, will also be
tested in the presence of costimulatory blockade. They hypothesize that these
multifaceted strategies will promote graft survival in the short term via the
induction of anergy and/or clonal deletion and result in donor specific
tolerance over the long term. They have strong preliminary results in non-human
primate (NHP) models demonstrating that co-stimulatory blockade via antiCD154
monotherapy allows for engraftment and long term insulin independence and
preservation of functional islet mass. Several monkeys treated with anti-CD154
for a period of 6 months to one year are maintaining islet and renal allograft
function after discontinuation of therapy, with no evidence of rejection. The
recent availability of this powerful immunointervention agent provides a unique
opportunity to explore the tolerogenic potential of costimulatory blockade and
other immunomodulatory strategies on human islet allograft survival in selected
pilot trials, aimed at identification of clinically relevant tolerogenic
protocols. To better accomplish the goals of this RFA, and in line with our
overall institutional mission, we have successfully established a network of
collaborations and partnerships with key institutions, including the
NIDDK/Navy, Harvard, Yale, Stanford, the University of Giessen, the University
of Alabama and the University of Florida. They propose the following specific
aims:

Specific Aim #1: To define the best immunomodulatory strategy that will allow
for permanent islet allograft survival, donor specific unresponsiveness in the
absence of chronic recipient immunosuppression and prevention of recurrent beta
cell autoimmune destruction.

Specific Aim #2: To assess metabolic function of successful intrahepatic islet
allografts.

Specific Aim #3: To study immune alterations that lead to tolerance in islet
allograft recipients.
StatusFinished
Effective start/end date7/1/005/31/09

Funding

  • National Institute of Diabetes and Digestive and Kidney Diseases: $935,038.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $954,541.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $1,025,208.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $1,055,963.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $1,087,641.00

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