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J Thorac Cardiovasc Surg 2000;119:709-719
© 2000 The American Association for Thoracic Surgery

CARDIOTHORACIC TRANSPLANTATION

MECHANISMS OF TOLERANCE INDUCTION AND PREVENTION OF CARDIAC ALLOGRAFT VASCULOPATHY IN MINIATURE SWINE: THE EFFECT OF AUGMENTATION OF DONOR ANTIGEN LOAD

From the Transplantation Biology Research Center,^a the Department of Pathology,^b and the Division of Cardiac Surgery,^c Massachusetts General Hospital, Harvard Medical School, Boston, Mass.

Supported in part by grants from the National Heart, Lung, and Blood Institute of National Institutes of Health (RO1-HL54211) and The Thoracic Surgery Foundation for Research and Education. Dr Menard is an Edward D. Churchill Surgical Research Fellow, Massachusetts General Hospital.

Address for reprints: Joren C. Madsen, MD, DPhil, Massachusetts General Hospital, Department of Surgery, EDR 105, Boston, MA 02114.

Objective: Cotransplantation of a donor kidney along with a heart allograft can induce tolerance to both organs and prevent cardiac allograft vasculopathy in miniature swine. To determine whether the tolerogenic effect of donor kidney cotransplantation was due to an effect specific to the kidney graft or to an increase in donor antigen load, we compared heart-kidney recipients with recipients receiving two class I disparate hearts or with recipients receiving donor peripheral mononuclear cells at the time of isolated heart transplantation.
Methods: Recipients of major histocompatibility complex class I disparate allografts received 12 days of cyclosporine (INN: ciclosporin; 10-13 mg/kg administered intravenously on days 0-11). Group 1 animals received a heart alone (n = 5). Group 2 animals received heart and kidney allografts (n = 4). Group 3 animals received two major histocompatibility complex–matched heart allografts (n = 4). Two double-heart recipients were thymectomized 21 days before transplantation. Group 4 animals received a heart allograft and an infusion of high-dose donor peripheral blood leukocytes (2.5 x 10⁹ cells/kg, n = 2).
Results: Vasculopathy developed in group 1 recipients and the allografts were rejected within 55 days. Group 2 recipients accepted their heart and kidney allografts indefinitely without vasculopathy. Euthymic recipients from group 3 accepted their hearts long-term (>190 and >197 days), but vascular lesions developed. In thymectomized recipients from group 3, the hearts were rejected in 63 and 96 days with severe vasculopathy. Group 4 recipients demonstrated transient macrochimerism but their hearts were rejected within 47 and 63 days.
Conclusions: The beneficial effects of donor kidney cotransplantation on cardiac allograft survival and prevention of cardiac allograft vasculopathy are likely to involve both an increase in donor antigen load and an effect specific to the kidney allograft.