HOW CYCLOSPORINE MODIFIES HISTOLOGICAL AND MOLECULAR EVENTS IN THE VASCULAR WALL DURING CHRONIC REJECTION OF RAT CARDIAC ALLOGRAFTS

Accelerated allograft arteriosclerosis (chronic rejection) has emerged as a major factor affecting long-term survival of human cardiac at lo grafts. The underlying mechanism of this disorder remains unclear. The purpose of this study was to investigate the effect of cyclosporine o n the development of cardiac allograft arteriosclerosis at the cellula r and molecular level. Heterotopic rat cardiac allografts from DA dono rs to WF recipients, with a strong genetic disparity in major histocom patibility complex and non-major histocompatibility complex loci, were used. The allograft recipients received triple-drug immmunosuppressio n consisting of methylprednisolone (0.5 mg/kg/day), azathioprine (2 mg /kg/day), and three different noses of cyclosporine A (CsA; 5, 10, and 20 mg/kg/day). The grafts were removed 3 months after transplantation and processed for histology and immunohistochemistry. Low dose CsA (5 mg/kg/day) was associated with a severe form of intimal cell accumula tion and intimal thickening in epicardial arteries and in smaller intr amyocardial arterioles with nearly occluded vessel lumens 3 months aft er transplantation. The intermediate dose CsA (10 mg/kg/day) significa ntly inhibited arterial intimal thickening but was not efficient in re ducing intimal cell accumulation. Instead, high nose CsA (20 mg/kg/day ) significantly inhibited all arteriosclerotic vascular wall changes i n the allografts. Immunohistochemistry revealed that the occluded epic ardial arteries of cardiac allografts with low dose Csa expressed VCAM -1 on the endothelium. Higher CsA doses significantly reduced the expr ession of endothelial VCAM-1. Neither ICAM-1 nor major histocompatibil ities complex class II were expressed. Perivascular arterial infiltrat es consisting of T helper cells and monocytes/macrophages were a chara cteristic finding in the allograft with low dose CsA. In the allograft s treated with higher doses of CsA, arterial perivascular infiltrates were seldom seen. Our results conclusively demonstrate that sufficient immunosuppression with CsA inhibits intimal thickening and intimal ce ll accumulation of long-surviving rat cardiac allografts in a dose-dep endent fashion. Arteriosclerotic alterations associated with increased expression of arterial endnothelial VCAM-1 were totally down-regulate d by high doses of CsA.