Acute vascular rejection of xenografts: roles of natural and elicited xenoreactive antibodies in activation of vascular endothelial cells and induction of procoagulant activity.
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.
Gollackner
Bernd
B
Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02215, USA.
Goh
Seo Kiat
SK
Qawi
Imrana
I
Buhler
Leo
L
Knosalla
Christoph
C
Daniel
Soizic
S
Kaczmarek
Elzbieta
E
Awwad
Michel
M
Cooper
David K C
DK
Robson
Simon C
SC
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
D000910:Antibodies, Heterophile; C045475:Griffonia simplicifolia lectins; D037121:Plant Lectins; D013925:Thromboplastin