Combination of clopidogrel and everolimus dramatically reduced the development of transplant arteriosclerosis

Abstract

Objectives: Our group has previously shown that platelet inhibition with clopidogrel reduced the formation of transplant arteriosclerosis (TxA). The aim of this study was to investigate whether a combination of cyclosporine, tacrolimus or everolimus with clopidogrel has a beneficial effect on the development of TxA. Methods: Fully allogeneic C57BL/6 (H2b) donor aortas were transplanted into CBA (H2k) recipients. Recipient mice were treated with cyclosporine (2mg/kg/d), tacrolimus (12mg/kg/d) and everolimus (0.05mg/kg/d) alone or in combination with clopidogrel (1mg/kg/d). Grafts were analysed by histology and morphometry on day 30 after transplantation. Results: In mice treated with clopidogrel alone, TxA was reduced as compared to untreated controls (intima proliferation 65%±8% vs. 79%±9% [control]/n=5). Daily application of everolimus significantly reduced the development of TxA (intima proliferation of 48%±19% vs. 79%±9% [control], n=5). Strikingly, the combination of clopidogrel and everolimus almost completely abolished the formation of TxA (intima proliferation: 16%±12% vs. 79%±9% [control], n=5). Tacrolimus alone (intima proliferation: 58%±17% vs. 79%±9% [control], n=5) and in combination with clopidogrel (intima proliferation: 30%±5% vs. 79%±9% [control], n=5) also showed a significant reduction. In contrast, daily application of cyclosporine didn't reduce the development of TxA compared to controls (intima proliferation: 74%±8% vs. 79%±9% [control], n=5). Conclusion: These results demonstrate that combination of clopidogrel and everolimus as well as tacrolimus can dramatically reduce the development of TxA in a mouse aortic allograft model.