Effect of an anti-C5a monoclonal antibody indicates a prominent role for anaphylatoxin in pulmonary xenograft dysfunction.
BACKGROUND
In contrast to renal or cardiac xenografts, the inhibition of complement using cobra venom factor (CVF) accelerates pulmonary xenograft failure. By activating C3/C5 convertase, CVF depletes complement while additionally generating C5a and other anaphylatoxins, to which pulmonary xenografts may be uniquely susceptible. The current study investigates the role of C5a in pulmonary xenograft failure in baboons.


METHODS
Left orthotopic pulmonary xenografts using swine lungs expressing human CD46 were performed in baboons receiving: I) no other treatment (n=4), II) immunodepletion (n=5), and III) immunodepletion plus a single dose of mouse anti-human C5a monoclonal antibody (anti-C5a, 0.6 mg/kg administered intravenously) (n=3). The extent to which anti-C5a inhibits baboon C5a was assessed in vitro using a hemolytic reaction involving baboon serum and porcine red blood cells and by ELISA.


RESULTS
Baboons in Group III exhibited significantly prolonged xenograft survival (mean=722+/-121 min, P=0.02) compared to baboons in Group I (mean=202+/-24 min) and Group II (mean=276+/-79 min). Furthermore, baboons in Groups I and II experienced pronounced hemodynamic compromise requiring inotropic support whereas those in Group III remained hemodynamically stable throughout experimentation without the need for additional pharmacologic intervention.


CONCLUSIONS
These findings indicate that C5a exacerbates pulmonary xenograft injury and compromises recipient hemodynamic status. Moreover, blockade of anaphylatoxins, such as C5a, offers a promising approach for future investigations aimed at preventing pulmonary xenograft injury in baboons.
Gaca
Jeffrey G
JG
Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
Appel
James Z
JZ
Lukes
Jeffrey G
JG
Gonzalez-Stawinski
Gonzalo V
GV
Lesher
Aaron
A
Palestrant
Daniel
D
Logan
John S
JS
Love
Stephanie D
SD
Holzknecht
Zoie E
ZE
Platt
Jeffrey L
JL
Parker
William
W
Davis
R Duane
RD
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000494:pharmacology*; D001777:Blood Coagulation; D001794:Blood Pressure; D015936:Complement C5a / Q000037:antagonists & inhibitors* / Q000276:immunology*; D004727:Endothelium / Q000098:blood supply / Q000276:immunology / Q000473:pathology; D006084:Graft Rejection / Q000276:immunology* / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D006085:Graft Survival; D006801:Humans; D007150:Immunohistochemistry; D016040:Lung Transplantation; D010215:Papio; D013552:Swine; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D015936:Complement C5a