Complement inhibition with an anti-C5 monoclonal antibody prevents hyperacute rejection in a xenograft heart transplantation model.
BACKGROUND
The present study was undertaken to determine whether anti-complement 5 (C5) monoclonal antibodies (mAb) prevent hyperacute rejection (HAR) in a rat-to-presensitized mouse heart transplantation model and whether these mAb, combined with cyclosporine (CsA) and cyclophosphamide (CyP), can achieve long-term graft survival.


METHODS
BALB/c mice were presensitized with 2x10(7) splenocytes from Lewis rats 14 days before grafting. Heart grafts from Lewis rats were heterotopically transplanted into BALB/c mice. Presensitized mice were treated with either anti-C5 mAb or a combination of anti-C5 mAb, CsA, and CyP. Controls included: presensitized mice with no treatment, presensitized mice treated with either CsA + CyP or IgG, and nonpresensitized mice with either no treatment or with CsA + CyP treatment.


RESULTS
Although typical features of HAR were evident in the presensitized grafts, the mAb completely inhibited complement activation and successfully prevented HAR. Despite complement inactivation, the graft was rejected on postoperative day 6 with acute vascular rejection (AVR) also known as delayed xenograft rejection (DXR). Notably, this type of rejection cannot be effectively overcome by CsA and CyP.


CONCLUSIONS
We conclude that (1) anti-C5 mAb prevents HAR, (2) AVR/DXR still occurs when HAR is prevented by complement inactivation, and (3) AVR/DXR cannot be overcome by conventional immunosuppression. These data suggest that anti-C5 mAb may be valuable for preventing HAR in future clinical xenotransplantation and that additional interventions may be required to address AVR/DXR.
Wang
H
H
Department of Surgery, The University of Western Ontario, London, Canada.
Rollins
S A
SA
Gao
Z
Z
Garcia
B
B
Zhang
Z
Z
Xing
J
J
Li
L
L
Kellersmann
R
R
Matis
L A
LA
Zhong
R
R
D000208:Acute Disease; D000818:Animals; D000910:Antibodies, Heterophile / Q000032:analysis; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D003182:Complement C5 / Q000276:immunology*; D003169:Complement Inactivator Proteins / Q000627:therapeutic use*; D006084:Graft Rejection / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects; D016027:Heart Transplantation / Q000276:immunology*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009206:Myocardium / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D014183:Transplantation, Heterologous / Q000276:immunology*; D016896:Treatment Outcome
D000910:Antibodies, Heterophile; D000911:Antibodies, Monoclonal; D003182:Complement C5; D003169:Complement Inactivator Proteins