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CD80/CD86 Costimulation Regulates Acute Vascular Rejection¹

Karoline A. Hosiawa^2,*,, Hao Wang^2,, Mark E. DeVries^*,, Bertha Garcia, Weihua Liu, Dejun Zhou^*, Ali Akram^**,, Jifu Jiang, Hongtao Sun, Mark J. Cameron, Robert Zhong^3,,,¶,|| and David J. Kelvin³

^* Division of Experimental Therapeutics, University Health Network, Toronto General Research Institute, Toronto General Hospital, Toronto, Ontario, Canada; Departments of Microbiology and Immunology, Department of Surgery, and Department of Pathology, University of Western Ontario, London, Ontario, Canada; ^¶ Multi-Organ Transplant Program, London Health Sciences Centre, London, Ontario, Canada; ^|| Transplantation and Regeneration Group, Lawson Health Research Institute, London, Ontario, Canada; ^# Transplant Group, Robarts Research Institute, London, Ontario, Canada; ^** Department of Immunology, University of Toronto, Toronto, Ontario, Canada; and Division of Infection, Injury, Immunity and Repair Research, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada

Xenotransplantation may provide the only solution to the shortage of human donor organs. Although hyperacute rejection associated with xenotransplantation can now be overcome, acute vascular rejection (AVR) remains a primary barrier to xenotransplantation. To date, standard immunosuppressive agents fail to block AVR or prolong xenograft survival. The present study was undertaken to determine the role of CD80/CD86 costimulatory molecules in regulating AVR. Lewis rat hearts were transplanted heterotopically into wild-type or IL-12, CD80- or CD86-deficient C57BL/6 mice. Wild-type recipients were treated with CD80 or CD86 neutralizing Ab with and without daily cyclosporin A (CsA, 15 mg/kg). Transplanted hearts in untreated wild-type recipients were rejected on postoperative days (POD) 17–21 and showed cell-mediated rejection (CMR) and AVR pathologies. In contrast, transplanted hearts in IL-12 and CD80 recipients or wild-type recipients treated with CD80 neutralizing Ab were rapidly rejected on POD 5 and 6 with AVR pathology. Interestingly, hearts transplanted into CD86 knockout recipients or wild-type recipients treated with CD86 neutralizing Ab underwent CMR on POD 17. Finally, blockade of CD86 but not CD80 rendered xenograft recipients sensitive to daily CsA therapy, leading to indefinite xenograft survival. To conclude, we demonstrate that AVR can be overcome by blocking the CD86 costimulatory pathway. Furthermore, we demonstrate that CD80 and CD86 have opposing roles in regulation of xenotransplantation rejection, where CD80 drives CMR and attenuates AVR while CD86 drives AVR. Most strikingly, indefinite xenograft survival can be achieved by suppressing AVR with CD86 neutralization in combination of CsA therapy, which inhibits CMR.

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