Prevention of acute vascular rejection by a functionally blocking anti-C5 monoclonal antibody combined with cyclosporine.
BACKGROUND
Inhibition of the complement cascade at C5 prevents formation of pro-inflammatory molecules C5a and C5b-9, which play a key role in allograft rejection. The present study was undertaken to determine whether blocking terminal complement with anti-C5 monoclonal antibody (mAb) alone or combined with cyclosporine (CsA) would prevent acute vascular rejection (AVR) in a mouse cardiac allograft model.


METHODS
C3H mouse hearts were transplanted into BALB/c mice and randomized into five groups with the following treatments: (1) no treatment; (2) CsA alone; (3) control mAb; (4) anti-C5 mAb alone; and (5) anti-C5 mAb and CsA.


RESULTS
Allografts in untreated or control mAb-treated recipients were rapidly rejected at 8.0+/-0.6 and 8.2+/-0.8 days, respectively. These grafts exhibited typical AVR, characterized by vasculitis, hemorrhage, and thrombosis. A high level of complement activity was also demonstrated in these animals. High-dose CsA was not able to inhibit complement activation or AVR, and grafts were rejected in 15.5+/-1.1 days. Anti-C5 monotherapy completely inhibited complement activation and attenuated AVR, but grafts were rejected in 8.3+/-0.5 days by acute cellular rejection. In contrast, a combination of anti-C5 mAb and CsA successfully achieved indefinite graft survival (>100 days). This combined therapy completely inhibited terminal complement activation and prevented both humoral- and cellular-mediated rejection.


CONCLUSIONS
Combination therapy of anti-C5 mAb and CsA achieves indefinite graft survival in a mouse cardiac allograft model. These data suggest that inhibition of terminal complement using anti-C5 mAb may be an effective therapeutic adjunct to prevent AVR in clinical transplantation.
Wang
Hao
H
Multi-Organ Transplant Program, London Health Sciences Centre, London, Ontario, Canada.
Jiang
Jifu
J
Liu
Weihua
W
Kubelik
Dalibor
D
Chen
Gang
G
Gies
David
D
Garcia
Bertha
B
Zhong
Robert
R
Rother
Russell P
RP
D000208:Acute Disease; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001808:Blood Vessels / Q000276:immunology / Q000473:pathology; D003182:Complement C5 / Q000276:immunology*; D016572:Cyclosporine / Q000627:therapeutic use*; D005434:Flow Cytometry; D006084:Graft Rejection / Q000517:prevention & control*; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology; D007518:Isoantibodies / Q000097:blood; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D014184:Transplantation, Homologous / Q000276:immunology
D000911:Antibodies, Monoclonal; D003182:Complement C5; D007518:Isoantibodies; D016572:Cyclosporine