Clopidogrel (Plavix®) significantly reduced the development of transplant arteriosclerosis in murine aortic allografts

Introduction: Platelets have been implicated to play a role in the pathogenesis of transplant arteriosclerosis. Therefore the aim of this study was to investigate if platelet inhibition has a beneficial effect on the development of this disease. Methods: Fully MHC mismatched C57BL/6 (H2b) donor aortas were transplanted into CBA (H2k) recipients and mice received different doses (1mg/kg, 10mg/kg, 20mg/kg) of Clopidogrel or control saline as a daily i.p. injection for 30 days. Blood was analysed at days 2, 7, 14 and 30 by a platelet aggregation test (ADP) for effectiveness of the treatment. Grafts were analysed by histology and morphometry on day 30 after transplantation. Intra-graft cytokine and chemokine mRNA production was analysed by RT-PCR on day 14 after transplantation. Results: After daily treatment with 1mg/kg clopidogrel platelet aggregation (ADP) was significantly reduced from day 7 onwards. This treatment also significantly reduced the development of transplant arteriosclerosis as compared to controls [intimal proliferation 66±7% (1mg/kg clopidogrel) vs. 77±5% (control) n=8; p=0.03]. Daily application of 10mg/kg and 20mg/kg clopidogrel also significantly reduced the development of transplant arteriosclerosis as compared to controls [intimal proliferation 61±11% (10mg/kg clopidogrel) vs. 54±10% (20mg/kg clopidogrel) vs. 77±5% (control) n=8; p=0.005]. Intra-graft cytokine production showed significantly lower ICAM-1, PDGFβ and IL-6 mRNA production in clopidogrel treated recipients. Conclusion: These results demonstrate that clopidogrel can effectively inhibit the formation of transplant arteriosclerosis in a murine aortic allograft model. Moreover, these findings have important clinical implications as patients suffering from transplant arteriosclerosis may benefit from treatment with this drug.