title: Evidence of human non-alpha-galactosyl antibodies involved in the hyperacute rejection of pig lungs and their removal by pig organ perfusion.
abstract: BACKGROUND
  Human natural xenoantibodies represent a major hurdle to the clinical application of pig lungs in transplantation by initiating hyperacute rejection within minutes to hours.
  
  
  OBJECTIVE
  The object was to compare pig organ perfusion and specific depletion of anti-alpha-galactosyl xenoantibodies for prevention of hyperacute rejection in the pig to human lung combination.
  
  
  METHODS
  Large White pig (20-25 kg) left lungs were removed and continuously ventilated and reperfused ex vivo either with (1) whole human blood previously perfused in situ through pig right lung (group I), liver (group II), or spleen (group III) or with (2) human plasma in vitro immunoabsorbed on columns containing alpha-galactosyl disaccharide (Gal-alpha-(1-3)Gal-beta-(CH2)3NH2; B disaccharide) (group IV). Each study group included 6 animals.
  
  
  RESULTS
  The in situ and in vitro preperfusions depleted anti-alpha-galactosyl xenoantibodies and all in situ perfused pig organs showed histologic signs of hyperacute rejection. After the ex vivo reperfusion, group I xenografts had a significantly (P < .001) longer functional and histologic survival than did xenografts in groups II, III, and IV. Human blood reperfusing group I xenografts had a significantly (P < 0.05) lower (1) decline of clotting factors and total circulating immunoglobulins, (2) total and membrane attack complex (C5b,6,7,8,9) complement activation, and (3) hemolysis. By Western blot analysis, the in situ lung preperfusion removed antibodies against non-alpha-galactosyl proteins of low molecular weight that were not eliminated by the alpha-galactosyl column.
  
  
  CONCLUSIONS
  Results demonstrate that specific depletion of anti-alpha-galactosyl antibodies alone incompletely protects pig lungs from hyperacute rejection. It is speculated that the more complete prevention of this rejection afforded by pig lung preperfusion relates to the removal of other, non-alpha-galactosyl antibodies.
authors.affiliation: Department of Thoracic and Vascular Surgery, Hôpital Marie-Lannelongue, Le Plessis Robinson, Paris-Sud University, France.
authors.forename: P
authors.initials: P
authors.lastname: Macchiarini
authors.forename: R
authors.initials: R
authors.lastname: Oriol
authors.forename: A
authors.initials: A
authors.lastname: Azimzadeh
authors.forename: V
authors.initials: V
authors.lastname: de Montpreville
authors.forename: R
authors.initials: R
authors.lastname: Rieben
authors.forename: N
authors.initials: N
authors.lastname: Bovin
authors.forename: M
authors.initials: M
authors.lastname: Mazmanian
authors.forename: P
authors.initials: P
authors.lastname: Dartevelle
mesh_terms: D000208:Acute Disease; D000818:Animals; D000910:Antibodies, Heterophile / Q000097:blood*; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology; D006801:Humans; D016040:Lung Transplantation / Q000276:immunology* / Q000473:pathology; D009926:Organ Preservation; D010477:Perfusion; D011659:Pulmonary Gas Exchange / Q000502:physiology; D013552:Swine; D014183:Transplantation, Heterologous; D014312:Trisaccharides / Q000276:immunology*
chemical_list: D000910:Antibodies, Heterophile; D014312:Trisaccharides; C076569:alpha-galactosyl epitope