Mechanisms of tolerance induction and prevention of cardiac allograft vasculopathy in miniature swine: The effect of augmentation of donor antigen load

Objective: Cotransplantation of a donor kidney along with a heart allograft can induce tolerance to both organs and prevent cardiac allograft vasculop athy in miniature swine. To determine whether the tolerogenic effect of don or kidney cotransplantation was due to an effect specific to the kidney gra ft or to an increase in donor antigen load, we compared heart-kidney recipi ents with recipients receiving two class I disparate hearts or with recipie nts receiving donor peripheral mononuclear cells at the time of isolated he art transplantation. Methods: Recipients of major histocompatibility complex class I disparate a llografts received 12 days of cyclosporine (INN: ciclosporin; 10-13 mg/kg a dministered intravenously on days 0-11). Group 1 animals received a heart a lone (n = 5). Group 2 animals received heart and kidney allografts (n = 4). Group 3 animals received two major histocompatibility complex-matched hear t allografts (n = 4), Two double-heart recipients were thymectomized 21 day s before transplantation. Group 4 animals received a heart allograft and an infusion of high-dose donor peripheral blood leukocytes (2.5 x 10(9) cells /kg, n = 2). Results: Vasculopathy developed in group I recipients and the allografts we re rejected within 55 days. Group 2 recipients accepted their heart and kid ney 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 wer e rejected in 63 and 96 days with severe vasculopathy. Group 4 recipients d emonstrated transient macrochimerism but their hearts were rejected within 47 and 63 days. Conclusions: The beneficial effects of donor kidney cotransplantation on ca rdiac allograft survival and prevention of cardiac allograft vasculopathy a re likely to involve both an increase in donor antigen load and an effect s pecific to the kidney allograft.