title: Effect of an anti-C5a monoclonal antibody indicates a prominent role for anaphylatoxin in pulmonary xenograft dysfunction.
abstract: BACKGROUND
  In contrast to renal or cardiac xenografts, the inhibition of complement using cobra venom factor (CVF) accelerates pulmonary xenograft failure. By activating C3/C5 convertase, CVF depletes complement while additionally generating C5a and other anaphylatoxins, to which pulmonary xenografts may be uniquely susceptible. The current study investigates the role of C5a in pulmonary xenograft failure in baboons.
  
  
  METHODS
  Left orthotopic pulmonary xenografts using swine lungs expressing human CD46 were performed in baboons receiving: I) no other treatment (n=4), II) immunodepletion (n=5), and III) immunodepletion plus a single dose of mouse anti-human C5a monoclonal antibody (anti-C5a, 0.6 mg/kg administered intravenously) (n=3). The extent to which anti-C5a inhibits baboon C5a was assessed in vitro using a hemolytic reaction involving baboon serum and porcine red blood cells and by ELISA.
  
  
  RESULTS
  Baboons in Group III exhibited significantly prolonged xenograft survival (mean=722+/-121 min, P=0.02) compared to baboons in Group I (mean=202+/-24 min) and Group II (mean=276+/-79 min). Furthermore, baboons in Groups I and II experienced pronounced hemodynamic compromise requiring inotropic support whereas those in Group III remained hemodynamically stable throughout experimentation without the need for additional pharmacologic intervention.
  
  
  CONCLUSIONS
  These findings indicate that C5a exacerbates pulmonary xenograft injury and compromises recipient hemodynamic status. Moreover, blockade of anaphylatoxins, such as C5a, offers a promising approach for future investigations aimed at preventing pulmonary xenograft injury in baboons.
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Gaca
authors.forename: James Z
authors.initials: JZ
authors.lastname: Appel
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Lukes
authors.forename: Gonzalo V
authors.initials: GV
authors.lastname: Gonzalez-Stawinski
authors.forename: Aaron
authors.initials: A
authors.lastname: Lesher
authors.forename: Daniel
authors.initials: D
authors.lastname: Palestrant
authors.forename: John S
authors.initials: JS
authors.lastname: Logan
authors.forename: Stephanie D
authors.initials: SD
authors.lastname: Love
authors.forename: Zoie E
authors.initials: ZE
authors.lastname: Holzknecht
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Platt
authors.forename: William
authors.initials: W
authors.lastname: Parker
authors.forename: R Duane
authors.initials: RD
authors.lastname: Davis
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000494:pharmacology*; D001777:Blood Coagulation; D001794:Blood Pressure; D015936:Complement C5a / Q000037:antagonists & inhibitors* / Q000276:immunology*; D004727:Endothelium / Q000098:blood supply / Q000276:immunology / Q000473:pathology; D006084:Graft Rejection / Q000276:immunology* / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D006085:Graft Survival; D006801:Humans; D007150:Immunohistochemistry; D016040:Lung Transplantation; D010215:Papio; D013552:Swine; D014183:Transplantation, Heterologous
chemical_list: D000911:Antibodies, Monoclonal; D015936:Complement C5a