Journal
AMERICAN JOURNAL OF TRANSPLANTATION
Volume 12, Issue 11, Pages 2909-2919Publisher
WILEY
DOI: 10.1111/j.1600-6143.2012.04213.x
Keywords
CD3 antibodies; immune tolerance; islet allografts; regulatory T cells
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Funding
- RISET consortium (Reprogramming the Immune System for the Establishment of Tolerance) from the European Commission (FP6)
- Fondation CENTAURE
- Juvenile Diabetes Research Foundation (JDRF)
- INSERM
- Fondation Day Solvay
- Dutch Kidney Foundation
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Despite remarkable progress in organ transplantation through the development of a wealth of immunosuppressive drugs highly effective at controlling acute rejection, two major problems still remain, the loss of transplants due to chronic rejection and the growing number of sensitized recipients due to previous transplants, transfusions or pregnancies. Induction of immune tolerance appears to be the only way to curb this complex situation. Here we describe that a therapy, already successfully used to restore immune tolerance to self-antigens in overt autoimmunity, is effective at promoting transplant tolerance. We demonstrate that a short low-dose course with CD3 antibodies started after transplantation, at the time of effector T cell priming to alloantigens, induces permanent acceptance of fully mismatched islet allografts. Mechanistic studies revealed that antigen-specific regulatory and effector T cells are differentially affected by the treatment. CD3 antibody treatment preferentially induces apoptosis of activated alloreactive T cells which is mandatory for tolerance induction. In contrast, regulatory T cells are relatively spared from CD3 antibody-induced depletion and can transfer antigen-specific tolerance thus arguing for their prominent role in sustaining long-term graft survival.
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