Complement inhibition with an anti-C5 monoclonal antibody prevents acute cardiac tissue injury in an ex vivo model of pig-to-human xenotransplantation.
Prevention of hyperacute xenograft rejection in the pig-to-primate combination has been accomplished by removal of natural antibodies, complement depletion with cobra venom factor, or prevention of C3 activation with the soluble complement inhibitor sCR1. Although these strategies effectively prevent hyperacute rejection, they do not address the relative contribution of early (C3a, C3b) versus late (C5a, C5b-9) activated complement components to xenogeneic organ damage. To better understand the role of the terminal complement components (C5a, C5b-9) in hyperacute rejection, an anti-human C5 mAb was developed and tested in an ex vivo model of cardiac xenograft rejection. In vitro studies demonstrated that the anti-C5 mAb effectively blocked C5 cleavage in a dose-dependent manner that resulted in complete inhibition of both C5a and C5b-9 generation. Addition of anti-C5 mAb to human blood used to perfuse a porcine heart prolonged normal sinus cardiac rhythm from a mean time of 25.2 min in hearts perfused with unmodified blood to 79,296, or > 360 min when anti-C5 mAb was added to the blood at 50 micrograms/ml, 100 micrograms/ml, or 200 micrograms/ml, respectively. In these experiments, activation of the classical complement pathway was completely inhibited. Hearts perfused with blood containing the highest concentration of anti-C5 mAb had no histologic evidence of hyperacute rejection and no deposition of C5b-9. These experiments suggest that the activated terminal complement components C5a and C5b-9, but not C3a or C3b, play a major role in tissue damage in this porcine-to-human model of hyperacute rejection. They also suggest that targeted inhibition of terminal complement activation by anti-C5 mAbs may be useful in clinical xenotransplantation.
Department of Surgery, University of Minnesota, Minneapolis 55455, USA.
T J
TJ
Kroshus
S A
SA
Rollins
A P
AP
Dalmasso
E A
EA
Elliott
L A
LA
Matis
S P
SP
Squinto
R M
RM
Bolman
D000208:Acute Disease; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000627:therapeutic use; D003167:Complement Activation; D003182:Complement C5 / Q000502:physiology*; D004730:Endothelium, Vascular / Q000276:immunology; D006084:Graft Rejection; D016027:Heart Transplantation / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007075:Immunoglobulin M / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009206:Myocardium / Q000276:immunology*; D010477:Perfusion; D013552:Swine; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D003182:Complement C5; D007074:Immunoglobulin G; D007075:Immunoglobulin M