title: Hyperacute lung rejection in the pig-to-human model 4: evidence for complement and antibody independent mechanisms.
abstract: BACKGROUND
  We assessed whether the combination of complement regulation and depletion of xenoreactive antibodies improves the outcome of pulmonary xenografts compared with either strategy alone.
  
  
  METHODS
  Lungs from pigs heterozygous (hDAF(+/-)) or homozygous (hDAF(+/+)) for the human decay accelerating factor transgene (hDAF) or their nontransgenic litter mates (hDAF(-/-)) were perfused with heparinized whole human blood. In additional groups, xenoreactive natural antibodies (XNA) were depleted by pig lung perfusion (hDAF(-/-)/AbAbs, hDAF(+/-)/AbAbs) before the experiment. This combined approach was augmented by adding soluble complement receptor 1 (sCR1) to the perfusate in one further group (hDAF(+/-)/AbAbs/sCR1).
  
  
  RESULTS
  HDAF(-/-) lungs perfused with unmodified human blood were rejected after 32.5 min (interquartile range, IQR 5 to 210). HDAF(+/-) lungs survived for 90 min (IQR 10 to 161, P = 0.54). Both groups showed a rapid rise in pulmonary vascular resistance (PVR), which is a characteristic feature of hyperacute rejection (HAR). This phenomenon was blunted in the hDAF(+/+) group, although survival (48 min, IQR 14 to 111) was not further prolonged. Antibody depletion (AbAbs) led to a significant increase in survival time (hDAF(-/-)/AbAbs: 315 min, IQR 230 to 427; hDAF(+/-)/AbAbs: 375 min, IQR 154 to 575), reduced PVR and less complement production. Addition of sCR1 reduced complement elaboration but did not further improve survival (200 min, IQR 128 to 580) and surprisingly tended to increase PVR.
  
  
  CONCLUSIONS
  Depletion of xenoreactive antibodies is more effective than membrane-bound complement regulation to blunt hyperacute rejection of pulmonary xenografts, but even the combined approach including soluble-phase complement inhibition is not sufficient to reliably prevent organ failure within hours. It therefore seems likely that other factors independent of antibody and complement contribute to HAR in this model.
authors.affiliation: Department of Cardiac and Thoracic Surgery, Vanderbilt University Med-ical Center and VAMC, Nashville, Tennessee, USA.
authors.forename: Steffen
authors.initials: S
authors.lastname: Pfeiffer
authors.forename: George L
authors.initials: GL
authors.lastname: Zorn
authors.forename: Kelly S A
authors.initials: KS
authors.lastname: Blair
authors.forename: Steve M
authors.initials: SM
authors.lastname: Farley
authors.forename: Guosheng
authors.initials: G
authors.lastname: Wu
authors.forename: Henk-Jan
authors.initials: HJ
authors.lastname: Schuurman
authors.forename: David J G
authors.initials: DJ
authors.lastname: White
authors.forename: Agnes M
authors.initials: AM
authors.lastname: Azimzadeh
authors.forename: Richard N
authors.initials: RN
authors.lastname: Pierson
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D003167:Complement Activation; D003165:Complement System Proteins / Q000276:immunology; D006084:Graft Rejection / Q000097:blood / Q000276:immunology* / Q000473:pathology; D006085:Graft Survival / Q000276:immunology; D006632:Histamine / Q000097:blood; D006801:Humans; D007150:Immunohistochemistry; D016040:Lung Transplantation / Q000276:immunology* / Q000473:pathology; D018448:Models, Immunological; D010477:Perfusion; D013552:Swine / Q000276:immunology; D013931:Thromboxanes / Q000097:blood; D013997:Time Factors; D014183:Transplantation, Heterologous / Q000276:immunology* / Q000473:pathology
chemical_list: D000906:Antibodies; D013931:Thromboxanes; D006632:Histamine; D003165:Complement System Proteins