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(Circulation. 2008;117:660-669.)
© 2008 American Heart Association, Inc.

Transplantation

Critical Role of Donor Tissue Expression of Programmed Death Ligand-1 in Regulating Cardiac Allograft Rejection and Vasculopathy

Jun Yang, MD, PhD; Joyce Popoola, MD, MRCP, PhD; Shakila Khandwala, PhD; Nidyanandh Vadivel, MD, MRCP; Vijay Vanguri, MD; Xueli Yuan, MD, PhD; Shirine Dada, MD; Indira Guleria, PhD; Chaorui Tian, MD, PhD; M. Javeed Ansari, MD, MRCP; Tahiro Shin, MD, PhD; Hideo Yagita, PhD; Miyuki Azuma, PhD; Mohamed H. Sayegh, MD; Anil Chandraker, MD, FRCP

From the Transplantation Research Center (J.Y., J.P., S.K., N.V., V.V., X.Y., S.D., I.G., C.T., M.J.A., M.H.S., A.C.), Renal Division, Brigham and Women’s Hospital, Children’s Hospital Boston, Harvard Medical School, Boston, Mass; the Department of Dermatology and Oncology (T.S.), Johns Hopkins University, School of Medicine, Baltimore, Md; the Department of Immunology (H.Y.), Juntendo University School of Medicine, Tokyo, Japan; and the Department of Molecular Immunology (M.A.), Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.

Correspondence to Mohamed H. Sayegh MD, Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital Boston, 221 Longwood Ave, Boston MA 02115. E-mail msayegh{at}rics.bwh.harvard.edu

Received September 20, 2007; accepted November 28, 2007.

Background— Allograft vasculopathy is a major limiting factor in the long-term success of cardiac transplantation. T cells play a critical role in initiation of cardiac allograft rejection and allograft vasculopathy. The negative T-cell costimulatory pathway PD-1:PDL1/PDL2 (programmed death-1:programmed death ligand-1/2) plays an important role in regulating alloimmune responses. We investigated the role of recipient versus donor PD-1 ligands in the pathogenesis of allograft rejection with emphasis on the role of tissue expression in regulating this alloimmune response in vivo.

Methods and Results— We used established major histocompatibility complex class II– and class I–mismatched models of vascularized cardiac allograft rejection, blocking anti-PDL1 and anti-PDL2 antibodies, and PDL1- and PDL2-deficient mice (as donors or recipients) to study the role of the PD-1:PDL1/PDL2 pathway in chronic rejection. We also used PDL1-deficient and wild-type mice and bone marrow transplantation to generate chimeric animals that express PDL1 exclusively on either hematopoietic or parenchymal cells. PDL1 but not PDL2 blockade significantly accelerated cardiac allograft rejection in the bm12-into-B6 and B6-into-bm12 models. Although wild-type cardiac allografts survived long term, PDL1^–/– donor hearts transplanted into wild-type bm12 mice exhibited accelerated rejection and vasculopathy associated with enhanced recipient T-cell alloreactivity. Interestingly, PDL1^–/– recipients did not exhibit an accelerated tempo of cardiac allograft rejection. Using chimeric animals as donors, we show that PDL1 expression on cardiac tissue alone significantly prolonged graft survival compared with full PDL1^–/– donor grafts in transplanted wild-type recipients.

Conclusions— This is the first report to demonstrate that expression of the negative costimulatory molecule PDL1 on donor cardiac tissue regulates recipient alloimmune responses, allograft rejection, and vasculopathy.

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CLINICAL PERSPECTIVE

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