HISTOLOGICAL CHARACTERIZATION AND PHARMACOLOGICAL CONTROL OF CHRONIC REJECTION IN XENOGENEIC AND ALLOGENEIC HEART-TRANSPLANTATION

Background. Chronic allograft rejection remains a major barrier to suc cessful long-term allograft transplantation in humans. Chronic allogra ft rejection is characterized by the appearance of arterial lesions wi th concentric intimal thickening. This study investigates the developm ent and control of chronic rejection in hamster cardiac xenografts tra nsplanted into Lewis rats. Methods. Chronic rejection in the xenograft model involves transplantation of hamster hearts into Lewis rats trea ted with leflunomide (Lef) continuously at 15 mg/kg/day. The allograft model involves transplantation of Lewis hearts into Fisher-334 rats t reated with cyclosporine (CsA) at 2.5 mg/kg for 5 days. Results. The a verage scores of arterial intimal thickening on day 45 after transplan tation were 1.89+/-0.43 in the xenograft and 2.50+/-0.72 in the allogr aft. The basic pathology of both xenografts and allografts undergoing chronic rejection was arterial intimal thickening comprising smooth mu scle cell proliferation, mononuclear cell infiltration, and fibrosis. The majority of cells infiltrating the arterial intima and myocar dium were T cells and macrophages. Compared with the allograft, intimal ed ema, matrix deposition and fibrinoid necrosis were specifically presen ted in the xenografts and generally involved the larger arteries. The predominant isotype of antibody deposited was IgM in xenografts and Ig G in allografts. When combined Lef and CsA therapy was initiated on da y 45 after transplantation, the changes of chronic rejection were reve rsed in both xenografts and allografts by day 90. The scores of intima l thickening were significantly reduced to 0.97+/-0.45 and 1.48+/-0.56 , respectively. Conclusions. We conclude that chronic rejection can be induced in xenografts under conditions of inadequate immunosuppressio n. Chronic rejection in xenografts involves arterial lesions that bear some histological similarities to, as well as differences from, those observed in chronically rejected allografts. Finally, combination the rapy with CsA and Lef reduced the incidence and severity of the intima l lesions in both chronically rejecting xenografts and allografts.