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* Multi-Organ Transplant Program, University Hospital, London Health Sciences Centre, London, Ontario, Canada;
Department of Surgery, University of Western Ontario, London, Ontario, Canada;
Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada;
Transplantation, Immunity and Regenerative Medicine, Lawson Health Research Institute, London Health Sciences Centre, London, Ontario, Canada;
¶ Department of Pathology, University of Western Ontario, London, Ontario, Canada; and
|| Alexion Pharmaceuticals, Cheshire, CT 06410
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by The Kidney Foundation of Canada, Heart and Stroke Foundation of Canada (NA5938), Roche Organ Transplantation Research Foundation, Canadian Institutes of Health Research, the Multi-Organ Transplant Program, London Health Sciences Centre, and Alexion Pharmaceuticals.
2 Address correspondence and reprint requests to Dr. Hao Wang, Department of Surgery, London Health Sciences Centre, University Hospital, 339 Windermere Road, P.O. Box 5339, London, Ontario, Canada N6A 5A5. E-mail address: hwang1{at}uwo.ca
3 Abbreviations used in this paper: AMR, Ab-mediated rejection; CsA, cyclosporine; CyP, cyclophosphamide; GVBS, gelatin Veronal-buffered saline; POD, postoperative day.
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  V. Pavlov, H. Raedler, S. Yuan, S. Leisman, W.-h. Kwan, P. N. Lalli, M. E. Medof, and P. S. Heeger Donor Deficiency of Decay-Accelerating Factor Accelerates Murine T Cell-Mediated Cardiac Allograft Rejection J. Immunol., October 1, 2008; 181(7): 4580 - 4589. [Abstract] [Full Text] [PDF]
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