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* Transplantation Research Center, Renal Division, Brigham and Women’s Hospital and Children’s Hospital Boston, Harvard Medical School, Boston, MA 02115;
Department of Surgery, University of Wuerzburg, Wuerzburg, Germany;
Department of Pathology, Brigham and Women’s Hospital, Boston, MA 02115;
Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan;
¶ Department of Molecular Immunology, Tokyo Medical and Dental University, Tokyo, Japan;
|| Department of Dermatology and Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287;
# Department of Pediatrics, Division of Bone Marrow Transplantation, University of Minnesota Hospitals and Clinics, Minneapolis, MN 55455; and
** Yale University Medical School, New Haven, CT 06510
The PD-1:PDL pathway plays an important role in regulating alloimmune responses but its role in transplantation tolerance is unknown. We investigated the role of PD-1:PDL costimulatory pathway in peripheral and a well established model of central transplantation tolerance. Early as well as delayed blockade of PDL1 but not PDL2 abrogated tolerance induced by CTLA4Ig in a fully MHC-mismatched cardiac allograft model. Accelerated rejection was associated with a significant increase in the frequency of IFN-
-producing alloreactive T cells and expansion of effector CD8+ T cells in the periphery, and a decline in the percentage of Foxp3+ graft infiltrating cells. Similarly, studies using PDL1/L2-deficient recipients confirmed the results with Ab blockade. Interestingly, while PDL1-deficient donor allografts were accepted by wild-type recipients treated with CTLA4Ig, the grafts developed severe chronic rejection and vasculopathy when compared with wild-type grafts. Finally, in a model of central tolerance induced by mixed allogeneic chimerism, engraftment was not abrogated by PDL1/L2 blockade. These novel data demonstrate the critical role of PDL1 for induction and maintenance of peripheral transplantation tolerance by its ability to alter the balance between pathogenic and regulatory T cells. Expression of PDL1 in donor tissue is critical for prevention of in situ graft pathology and chronic rejection.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants R01-AI51559, R01-AI34495, 2 R37 HL56067, R01-HL63452, P01-AI041521, and P01-AI56299. N.N. is a recipient of the American Heart Association Scientist Development Grant and National Institutes of Health 1K08AI064335.
2 Address correspondence and reprint requests to Dr. Nader Najafian, Brigham and Women’s Hospital, Transplantation Research Center, EBRC, 221 Longwood Avenue, 3rd Floor, Boston, MA 02115. E-mail address: nnajafian{at}rics.bwh.harvard.edu
3 Abbreviations used in this paper: PD-1, programmed death 1; MST, median survival time.
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