title: Ischemia-reperfusion injury accelerates human antibody-mediated transplant vasculopathy.
abstract: BACKGROUND
  The pathogenesis of transplant vasculopathy (TV) is a multifactorial process. We hypothesized that ischemia-reperfusion injury and antibody-mediated damage contribute to the development of TV.
  
  
  METHODS
  Human vessels were procured from nine separate donors undergoing cardiac surgery and stored in saline solution on ice until transplantation. BALB/c Rag2IL-2Rγ mice were transplanted with a human vessel graft on day 0. Purified anti-human leukocyte antigen class I antibody (W6/32), isotype control antibody, or saline was injected into recipient mice weekly until day 42, at which point the degree of intimal expansion (IE) of vessels was assessed by histologic analysis.
  
  
  RESULTS
  We found that a prolonged cold ischemia time (6-12 hr) alone did not induce IE. In mice that received antibody where vessels were transplanted within 6 hr of procurement, no IE was observed. By contrast, in vessels exposed to more than 6 hr cold ischemia, both W6/32 antibody (30.4%±6.9%) and isotype control antibody (39.5%±6.0%) promoted significant IE (P<0.05 vs. saline [12.4%±1.7%]). Importantly, the isotype control antibody did not cross-react with human tissue. Interestingly, the number of mouse Fc-receptor-positive cells was significantly increased in human vessels exposed to more than 6 hr cold ischemia but only in the presence of antibody (P<0.05).
  
  
  CONCLUSIONS
  Antibody, regardless of its specificity, may promote IE in human vessels that are injured through cold ischemia via interaction with Fc-receptor-positive cells. This highlights the importance of controlling the degree of cold ischemia in clinical transplantation in an effort to reduce the risk of TV development.
authors.affiliation: Transplantation Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, UK.
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Goto
authors.forename: Fadi
authors.initials: F
authors.lastname: Issa
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: Heidt
authors.forename: David
authors.initials: D
authors.lastname: Taggart
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Wood
mesh_terms: D000818:Animals; D000910:Antibodies, Heterophile / Q000276:immunology; D000918:Antibody Specificity; D001012:Aorta, Abdominal / Q000473:pathology / Q000601:surgery*; D050377:Cold Ischemia; D003429:Cross Reactions / Q000276:immunology; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D008297:Male; D008323:Mammary Arteries / Q000473:pathology / Q000637:transplantation*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011183:Postoperative Complications / Q000276:immunology* / Q000473:pathology; D011961:Receptors, Fc / Q000276:immunology; D015427:Reperfusion Injury / Q000276:immunology* / Q000473:pathology; D014183:Transplantation, Heterologous; D058017:Vascular Grafting / Q000379:methods*
chemical_list: D000910:Antibodies, Heterophile; D004268:DNA-Binding Proteins; D015395:Histocompatibility Antigens Class I; C499308:Rag2 protein, mouse; D011961:Receptors, Fc