title: CD80/CD86 costimulation regulates acute vascular rejection.
abstract: 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.
authors.affiliation: Division of Experimental Therapeutics, University Health Network, Toronto General Research Institute, Toronto General Hospital, Toronto, Ontario, Canada.
authors.forename: Karoline A
authors.initials: KA
authors.lastname: Hosiawa
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Mark E
authors.initials: ME
authors.lastname: DeVries
authors.forename: Bertha
authors.initials: B
authors.lastname: Garcia
authors.forename: Weihua
authors.initials: W
authors.lastname: Liu
authors.forename: Dejun
authors.initials: D
authors.lastname: Zhou
authors.forename: Ali
authors.initials: A
authors.lastname: Akram
authors.forename: Jifu
authors.initials: J
authors.lastname: Jiang
authors.forename: Hongtao
authors.initials: H
authors.lastname: Sun
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Cameron
authors.forename: Robert
authors.initials: R
authors.lastname: Zhong
authors.forename: David J
authors.initials: DJ
authors.lastname: Kelvin
mesh_terms: D000208:Acute Disease; D000818:Animals; D000906:Antibodies / Q000276:immunology*; D018122:B7-1 Antigen / Q000502:physiology*; D051940:B7-2 Antigen / Q000502:physiology*; D016572:Cyclosporine / Q000494:pharmacology; D006084:Graft Rejection / Q000209:etiology*; D006085:Graft Survival; D016027:Heart Transplantation / Q000276:immunology*; D007074:Immunoglobulin G / Q000097:blood; D007371:Interferon-gamma / Q000502:physiology; D018664:Interleukin-12 / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D011917:Rats, Inbred Lew; D013601:T-Lymphocytes / Q000276:immunology; D014183:Transplantation, Heterologous / Q000276:immunology*
chemical_list: D000906:Antibodies; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D007074:Immunoglobulin G; D018664:Interleukin-12; D007371:Interferon-gamma; D016572:Cyclosporine