Inhibition of terminal complement components in presensitized transplant recipients prevents antibody-mediated rejection leading to long-term graft survival and accommodation.
Ab-mediated rejection (AMR) remains the primary obstacle in presensitized patients following organ transplantation, as it is refractory to anti-T cell therapy and can lead to early graft loss. Complement plays an important role in the process of AMR. In the present study, a murine model was designed to mimic AMR in presensitized patients. This model was used to evaluate the effect of blocking the fifth complement component (C5) with an anti-C5 mAb on prevention of graft rejection. BALB/c recipients were presensitized with C3H donor skin grafts 7 days before heart transplantation from the same donor strain. Heart grafts, transplanted when circulating anti-donor IgG Abs were at peak levels, were rejected in 3 days. Graft rejection was characterized by microvascular thrombosis and extensive deposition of Ab and complement in the grafts, consistent with AMR. Anti-C5 administration completely blocked terminal complement activity and local C5 deposition, and in combination with cyclosporine and short-term cyclophosphamide treatment, it effectively prevented heart graft rejection. These recipients achieved permanent graft survival for >100 days with normal histology despite the presence of systemic and intragraft anti-donor Abs and complement, suggesting ongoing accommodation. Furthermore, double-transplant experiments demonstrated that immunological alterations in both the graft and the recipient were required for successful graft accommodation to occur. These data suggest that terminal complement blockade with a functionally blocking Ab represents a promising therapeutic approach to prevent AMR in presensitized recipients.
Wang
Hao
H
Multi-Organ Transplant Program, University Hospital, London Health Sciences Centre, London, Ontario, Canada. hwang1@uwo.ca
Arp
Jacqueline
J
Liu
Weihua
W
Faas
Susan J
SJ
Jiang
Jifu
J
Gies
David R
DR
Ramcharran
Siobhan
S
Garcia
Bertha
B
Zhong
Robert
R
Rother
Russell P
RP
D000818:Animals; D000906:Antibodies / Q000276:immunology*; D003165:Complement System Proteins / Q000378:metabolism*; D003520:Cyclophosphamide / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D006085:Graft Survival / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D009336:Necrosis / Q000276:immunology / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016038:Skin Transplantation / Q000276:immunology / Q000473:pathology; D015996:Survival Rate; D013997:Time Factors; D014184:Transplantation, Homologous / Q000276:immunology
D000906:Antibodies; D019253:Proto-Oncogene Proteins c-bcl-2; D016572:Cyclosporine; D003520:Cyclophosphamide; D003165:Complement System Proteins