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J Thorac Cardiovasc Surg 1998;115:1342-1349
© 1998 Mosby, Inc.
CARDIAC AND PULMONARY REPLACEMENT |
From the Cardiac Transplantation Research Laboratory, Division of Cardiothoracic Surgery, Department of Surgery,a the Department of Pathology,c and the Department of Radiation Medicine,d Loma Linda University Medical Center, Loma Linda, Calif., and the Sandoz Center for Immunobiology, New England Deaconess Hospital, Harvard Medical School, Boston, Mass.b
Presented in part at the Fourth International Congress for Xenotransplantation, Sept. 7-11, 1997, Nantes, France.
Received for publication Dec. 5, 1997. Accepted for publication Jan. 15, 1998. Address for reprints: Steven R. Gundry, MD, Department of Surgery, Loma Linda University Medical Center, 11234 Anderson St., Loma Linda, CA 92354.
Abstract
Objective: Our objectives were to study delayed xenograft rejection and the effectiveness of pretransplantation total lymphoid irradiation combined with immunosuppression on rejection in a pig-to-baboon cardiac xenograft model.
Methods: Baboons were treated with pretransplantation total lymphoid irradiation, cyclosporine A (INN: ciclosporin), and methotrexate. Orthotopic pig-to-baboon cardiac transplantations were performed after depletion of circulating xenoreactive natural antibody by pretransplantation donor organ hemoperfusion. Tissue samples were collected for immunologic and immunopathologic evaluation.
Results: Pig cardiac xenografts survived more than 18 and 19 days without evidence of hyperacute rejection. Immunologic analysis of serum samples demonstrated that circulating xenoreactive natural antibody levels did not return to pretransplantation levels. The production of xenoreactive natural antibodies from the recipient's splenocytes was inhibited completely. Histologic examination of xenografts showed the feature of acute vascular rejection. Immunohistochemical studies demonstrated infiltration of cardiac xenografts by large numbers of macrophages, small numbers of natural killer cells, and a few T cells. The infiltrating macrophages also showed expression of interleukin-1 and tumor necrosis factor. Diffuse deposition of immunoglobulin G, C1Q, C3, and fibrin on xenograft vasculature was observed. Interleukin-2 expression was not found in rejected cardiac xenografts. Xenograft endothelial cells also showed evidence of activation (expression of cytokines interleukin-1 and tumor necrosis factor).
Conclusions: This study demonstrates prolonged discordant cardiac xenograft survival and delayed xenograft rejection in a pig-to-baboon model. The delayed xenograft rejection is mediated by both humoral and cellular mechanisms. Pretransplantation total lymphoid irradiation combined with cyclosporine A and methotrexate can inhibit xenoreactive natural antibody production but not elicited antipig antibody production and the xenoreactivity of macrophages.
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