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(Circulation. 2005;112:320-331.)
© 2005 American Heart Association, Inc.

Cardiovascular Surgery

Inhibition of Polymorphonuclear Leukocyte–Mediated Graft Damage Synergizes With Short-Term Costimulatory Blockade to Prevent Cardiac Allograft Rejection

Tarek El-Sawy, PhD; John A. Belperio, MD; Robert M. Strieter, MD; Daniel G. Remick, MD; Robert L. Fairchild, PhD

From the Department of Immunology (T.E.-S., R.L.F.), Lerner Research Institute and Glickman Urological Institute (R.L.F.), The Cleveland Clinic Foundation, and Department of Pathology (T.E.-S., R.L.F.), Case Western Reserve University School of Medicine, Cleveland, Ohio; Division of Pulmonary Medicine, Department of Medicine, University of California at Los Angeles School of Medicine, Los Angeles (J.A.B., R.M.S.); and Department of Pathology, University of Michigan Medical School, Ann Arbor (D.G.R.).

Correspondence to Tarek El-Sawy, Department of Immunology, NB3-30, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195. E-mail tarek{at}case.edu

Received October 25, 2004; revision received March 29, 2005; accepted April 4, 2005.

Background— The early inflammatory response during reperfusion of cardiac allografts is initiated by the infiltration of polymorphonuclear leukocytes (PMNs) into the graft. The impact of early PMN infiltration on allograft rejection compared with long-term graft survival remains poorly understood.

Methods and Results— We tested the role of CXCR2, the receptor for 2 PMN attractant chemokines, KC/CXCL1 and MIP-2/CXCL2, on intragraft inflammation and vascularized cardiac allograft rejection in a murine model. Compared with allografts retrieved from control recipients, both PMN infiltration and intragraft proinflammatory cytokine expression were significantly attenuated in allografts from CXCR2-antisera–treated wild-type or from CXCR2^–/– recipients. Adoptive transfer of alloantigen-primed T cells rapidly infiltrated and rejected allografts in control recipients, but T-cell infiltration was significantly decreased in recipients depleted of PMNs at transplantation. The influence of early PMN-mediated inflammation on the therapeutic efficacy of costimulatory blockade to prevent allograft rejection was tested. Short-term treatment of recipients with anti-CD154 mAb or CTLA-4 Ig induced modest prolongation of cardiac allograft survival. However, CD154 mAb or CTLA-4 Ig treatment, combined with either peritransplantation PMN depletion or antibodies specific for KC/CXCL1 plus MIP-2/CXCL2, prolonged cardiac allograft survival beyond 100 days.

Conclusions— Results suggest that strategies attenuating PMN-mediated tissue damage during reperfusion significantly improve the efficacy of short-term costimulatory blockade to prevent T-cell–mediated rejection of cardiac allografts.

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