Murine cytomegalovirus infection leads to elevated levels of transplant arteriosclerosis in a murine aortic allograft model

Introduction: In clinical studies cytomegalovirus infection after heart transplantation is considered as risk factor for developing transplant arteriosclerosis (TxA), the hallmark feature of chronic rejection. The aim of this study was to investigate the effect of murine cytomegalovirus (MCMV) on TxA in an experimental aortic allograft model in the absence and presence of immune suppression. Methods: MHC-class-I mismatched C.B10-H2(b)/LilMcdJ donor aortas were transplanted into BALB/c mice. Recipients were infected with an isolate of Smith-MCMV 7 days and harvested 21 and 40 days after transplantation, resp. In one group animals received a daily dose of Everolimus (0,05 mg/kg/d) to facilitate viral infection. Grafts were analyzed by histology, morphometry and immunofluorescence on day 40 after transplantation. Intra-graft cytokine mRNA production was analyzed by RT-PCR on day 21 after transplantation. Persistence of MCMV infection was confirmed by Taqman-PCR. Results: Significant amounts of TxA were present in all experimental groups with and without immunosuppression. After infection with MCMV there was significantly more intimal proliferation as compared to uninfected controls [83,5±5,1% (MCMV+) vs. 43,9±9.6% (MCMV-)] indicating MCMV as an important risk factor for the development of TxA. Under immunosuppression MCMV infection still pronounced significantly more intimal proliferation [52,5±7,3% (MCMV+) vs. 20,2±1,7% (MCMV-)]. Intragraft mRNA expression showed significant higher production of E-selectin, Interleukin 4, ICAM-1 and VCAM-1 when infected with MCMV. Conclusion: These data suggest that MCMV infection plays an important role in the development of TxA.