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* Multi-Organ Transplant Program, University Hospital and
Transplantation, Immunity, and Regenerative Medicine, Lawson Health Research Institute, London Health Sciences Centre, London, Ontario, Canada;
Department of Surgery,
Department of Pathology, and
¶ Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada; and
|| Medistem Laboratories, San Diego, CA 92122
We report on a novel approach aimed at preventing acute vascular rejection (AVR), one of the major unresolved hurdles of clinical transplantation. In a C3H-to-BALB/c heterotopic heart transplant model, we demonstrate that free bone transplantation combined with cyclosporin A suppresses antidonor Ab responses, induces indefinite cardiac allograft survival (>100 days), and preserves graft architecture. In contrast, untreated- or cyclosporin A alone-treated recipients rejected their cardiac grafts on days 7.7 ± 0.6 and 15.5 ± 1.1, respectively, with graft histology indicative of AVR. Splenic dendritic cells from nonrejecting recipients expressed low levels of MHC II, CD40, and CD86, reduced ability to stimulate donor cell proliferation, and augmented IL-10 production of responding T cells in vitro. Adoptive transfer of dendritic cells from long-term surviving recipients 1 day before cardiac grafting was able to confer hyporesponsiveness to naive BALB/c recipients of cardiac allografts. To determine whether graft survival was associated with hematopoietic or stromal elements of the transplanted free bone, we administered isolated bone marrow mononuclear cells or free bone that was irradiated to deplete hematopoietic elements. Although bone marrow mononuclear cells had no effect on cardiac graft survival, irradiated free bone transplantation was capable of prolonging graft survival. Most interestingly, the prolongation effect was Ag nonspecific, because third party irradiated bone graft was also effective. Due to the fact that current immunosuppressive approaches are clinically ineffective at preventing AVR, this study provides promise for further investigations of BM components as a means of addressing a currently unmet medical need.
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 Heart and Stroke Foundation of Ontario Grants NA5938 and T6318, the Roche Organ Transplantation Research Foundation, the Kidney Foundation of Canada, the Canada Foundation for Innovation, and a Multi-Organ Transplant Program Research Grant from the London Health Sciences Centre.
2 Address correspondence and reprint requests to Dr. Hao Wang, Department of Surgery, University Hospital, London Health Sciences Centre, 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: AVR, acute vascular rejection; ACR, acute cellular rejection; BM, bone marrow; CsA, cyclosporin A; DC, dendritic cell; eGFP, enhanced GFP; HSC, hematopoietic stem cell; MSC, mesenchymal stem cell; POD, postoperative day.
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