Porcine cytomegalovirus and coagulopathy in pig-to-primate xenotransplantation.
BACKGROUND
A rapidly progressive disorder termed consumptive coagulopathy (CC) has been observed frequently in pig-to-baboon renal xenotransplantation. CC may be initiated by endothelial activation and induction of procoagulant factors after immunologic injury or infection, or by molecular incompatibilities between porcine coagulation proteins and primate clotting factors. The activation of porcine (P) cytomegalovirus (PCMV) and baboon (B) CMV infections has been documented in pig-to-primate xenotransplantation. The purpose of this study was to determine the contribution of PCMV and BCMV to CC.


METHODS
Endothelial activation was assessed by means of measurement of porcine tissue factor (pTF) in a functional assay in primary porcine aortic endothelial cells (PAEC) in vitro. Renal xenografts and native kidneys were studied by immunohistochemistry in immunosuppressed swine and baboons. BCMV and PCMV DNA was measured by quantitative molecular assays using real-time polymerase chain reaction.


RESULTS
In vitro, infection of PAEC with PCMV resulted in a significant increase of pTF expression. In vivo, pTF increase occurred without the activation of PCMV in two xenografts, and in four grafts no pTF was detected despite PCMV activation. All animals with graft pTF increase developed CC. BCMV activation in the baboon xenograft recipients did not correlate with CC or pTF increase. Control pigs and baboons had activation of PCMV and BCMV, respectively, but without coagulation abnormalities.


CONCLUSIONS
PCMV induces endothelial cell activation in vitro with procoagulant expression. However, in vivo, CC and pTF induction has an uncertain relationship to increased replication of PCMV within a xenograft. Although the data do not exclude a contributory role of PCMV in CC, other mechanisms are also likely to contribute to coagulopathies observed in pig-to-primate xenotransplantation.
Gollackner
Bernd
B
Transplantation Biology Research Center, Massachusetts General Hospital-Harvard Medical School, Boston, MA 02114, USA.
Mueller
Nicolas J
NJ
Houser
Stuart
S
Qawi
Imrana
I
Soizic
Daniel
D
Knosalla
Christoph
C
Buhler
Leo
L
Dor
Frank J M F
FJ
Awwad
Michel
M
Sachs
David H
DH
Cooper
David K C
DK
Robson
Simon C
SC
Fishman
Jay A
JA
D000818:Animals; D030801:Animals, Genetically Modified; D003587:Cytomegalovirus / Q000235:genetics / Q000302:isolation & purification*; D003586:Cytomegalovirus Infections / Q000503:physiopathology*; D004279:DNA, Viral / Q000032:analysis; D006085:Graft Survival / Q000502:physiology; D007165:Immunosuppression Therapy; D007668:Kidney / Q000473:pathology / Q000601:surgery; D016030:Kidney Transplantation; D010215:Papio; D011183:Postoperative Complications / Q000503:physiopathology / Q000821:virology; D013552:Swine; D013556:Swine, Miniature; D013921:Thrombocytopenia / Q000503:physiopathology*; D014183:Transplantation, Heterologous
D004279:DNA, Viral