title: Acute vascular rejection of xenografts: roles of natural and elicited xenoreactive antibodies in activation of vascular endothelial cells and induction of procoagulant activity.
abstract: BACKGROUND
  Hyperacute rejection of vascularized discordant xenografts can now be effectively managed. However, acute vascular rejection (AVR) then ensues, resulting in graft destruction, coagulopathy, or both within weeks. The aim of this study was to determine associations between humoral responses to the xenograft and the induction of AVR, coagulopathy, or both.
  
  
  METHODS
  In vitro, heat-inactivated, naive or sensitized baboon sera containing xenoreactive natural or elicited antibodies were used to activate porcine aortic endothelial cells (PAEC) in vitro. Tissue factor expression on PAEC was determined as an index of heightened procoagulant activity. In vivo, porcine renal xenografts were transplanted into immunosuppressed baboons, and at the time of rejection or the development of a consumptive coagulopathy, biopsy specimens were obtained for studies of xenoreactive antibody binding and tissue factor expression.
  
  
  RESULTS
  In vitro, incubation of PAEC with naive baboon sera containing natural anti-Galalpha1,3Gal (Gal) antibodies resulted in minimal tissue factor induction; the addition of complement boosted procoagulant responses. Elicited xenoreactive antibodies, and to non-Gal epitopes alone, induced high amounts of procoagulant activity on PAEC; the addition of complement resulted in overt cytotoxicity. In vivo, AVR was associated with xenoreactive antibody deposition in the graft. When vascular endothelial binding of xenoreactive antibody was combined with the expression of tissue factor, consumptive coagulopathy developed irrespective of histopathologic features of AVR.
  
  
  CONCLUSIONS
  Our in vitro results indicate that elicited antibodies, potentially to non-Gal epitopes, induce endothelial cell activation and tissue factor expression; in vivo, a consumptive coagulopathy occurred when there was xenoreactive antibody deposition and increase of tissue factor.
authors.affiliation: Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Bernd
authors.initials: B
authors.lastname: Gollackner
authors.forename: Seo Kiat
authors.initials: SK
authors.lastname: Goh
authors.forename: Imrana
authors.initials: I
authors.lastname: Qawi
authors.forename: Leo
authors.initials: L
authors.lastname: Buhler
authors.forename: Christoph
authors.initials: C
authors.lastname: Knosalla
authors.forename: Soizic
authors.initials: S
authors.lastname: Daniel
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Kaczmarek
authors.forename: Michel
authors.initials: M
authors.lastname: Awwad
authors.forename: David K C
authors.initials: DK
authors.lastname: Cooper
authors.forename: Simon C
authors.initials: SC
authors.lastname: Robson
mesh_terms: D000208:Acute Disease; D000818:Animals; D000910:Antibodies, Heterophile / Q000276:immunology*; D001011:Aorta; D001769:Blood; D001778:Blood Coagulation Disorders / Q000276:immunology*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D006084:Graft Rejection / Q000473:pathology; D007114:Immunization; D016030:Kidney Transplantation; D010215:Papio; D037121:Plant Lectins / Q000494:pharmacology; D013552:Swine; D013925:Thromboplastin / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D000910:Antibodies, Heterophile; C045475:Griffonia simplicifolia lectins; D037121:Plant Lectins; D013925:Thromboplastin