Dose-dependent suppression of transplant arteriosclerosis in aorta-allografted, cholesterol-clamped rabbits - Suppression not eliminated by the cholesterol-raising effect of cyclosporine

Cyclosporine may suppress transplant arteriosclerosis; however, it also raises plasma cholesterol, which could promote the disease. Our aim was to test these hypotheses experimentally. In experiment 1 (n=34), cholesterol was clamped at a human level of 5 to 7 mmol/L, and rabbits were given either saline or cyclosporine in a low, medium, or high dose. In experiment 2 (n=15), in which dietary cholesterol was fixed at 0.05 g.kg(-1).d(-1), and experiment 3 (n=16), in which no dietary cholesterol was added to the chow, rabbits were given either medium-dose cyclosporine, saline, or vehicle. The duration of each experiment was 5 weeks. In experiment 1, cyclosporine attenuated the development of transplant arteriosclerosis dose dependently (trend test: P<.0001). Cyclosporine also suppressed, in a dose-dependent manner, the activation of the immune system (trend test: P<.05) and the presence of T lymphocytes (trend test: P<.0001) and macrophages in the intima (trend test: P<.01). Despite a higher plasma cholesterol level in cyclosporine-treated rabbits compared with saline-treated rabbits in both experiment 2 (4.9 versus 2.9 mmol/L) and experiment 3 (1.6 versus 0.8 mmol/L), transplant arteriosclerosis was significantly reduced by cyclosporine (Mann-Whitney U test: P<.05 and P<.05). These results suggest that cyclosporine suppresses experimental transplant arteriosclerosis dose dependently. Accordingly, in the assessment of the optimal cyclosporine dose to heart-transplanted patients, it should be taken into account that a dose reduction may promote transplant arteriosclerosis.