COSTIMULATION BLOCKADE FOR PRIMATE RENAL TRANSPLANTATION

Project: Research project

Project Details

Description

Current treatments to prevent allograft rejection while quite effective
are nevertheless costly, associated with significant systemic toxicity,
and indiscriminately impair immune system function so that transplant
recipients are at increased risk for a variety of infectious illnesses and
cancers. Furthermore, traditional immunosuppressive therapies have proven
unable to prevent the rejection of potentially curative islet transplants
in individuals with insulin dependent diabetes mellitus (IDDM). Rodent and
non-human primate model studies have suggested that anti-CD154 (CD40L)
antibody-based treatments, alone or in combination with other immune
system modulators may significantly improve the approach to patients
requiring health sustaining allo-transplants. Preliminary data suggests
that this therapy may more specifically impair the anti-graft immune
response, can be administered intermittently, and may be associated with
less toxicity. Our overall goal is to develop this novel therapy for
clinical application. We will study highly relevant non-human primate
islet and kidney allograft models, transitioning into clinical trials as
warranted by preclinical studies. Among the several critical questions to
be addressed: (1) what is the immunological mechanism underlying the
prevention of allograft rejection?. (2) are anti-CD154-based therapies
safe and effective when co-administered with "traditional"
immunosuppressive agents including calcineurin phosphatase inhibitors,
glucocorticoids, and/or mycophenolate mofetil?. (3) is the efficacy of
anti-CD154-based therapies enhanced by increasing the donor antigen load
in the form of co-administered donor-specific bone marrow? (4) is the
efficacy of anti-CD154-based therapies enhanced by agents that interfere
with the B7 receptors (CD80 and CD86) ability to interact with their
counter-receptors and CTLA4 (CD152)? (5) how specific is the immune
inhibition? (6) will anti-CD154-based therapy reverse and/or decrease the
incidence of chronic rejection?. (7) can rejection episodes occurring
following induction therapy with anti-CD154 can be safely rescued?. and
(8) are anti-CD154 antibody mediated effects the result of blocking
CD154's interaction with CD40?. direct effects on cells expressing CD154?.
or both?
StatusFinished
Effective start/end date9/30/988/31/04

Funding

  • National Institute of Allergy and Infectious Diseases: $1,349,210.00

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