Reduced transplant arteriosclerosis after treatment with MMF and MMF in combination with ganciclovir in a mouse aortic transplant model

Abstract

Objectives: The aim of this study was to investigate whether Ganciclovir and Mycophenolate Mofetil (MMF), alone and in combination, have a beneficial influence on the development of transplant arteriosclerosis (TxA). Methods: Fully allogeneic C57BL/6 (H2b) donor aortas were transplanted into CBA (H2k) recipients. Recipient mice were treated with a single medication of MMF (100mg/kg or 300mg/kg) or a combination of MMF and Ganciclovir (10mg/kg Ganciclovir and 100mg/kg MMF or 72mg/kg Ganciclovir and 300mg/kg MMF) per day. Grafts were analysed by histology and morphometry on day 30 after transplantation. A potential effect of MMF or Ganciclovir on Tregs was investigated by FACS analysis. Results: Two doses of 150mg/kg MMF per day significantly reduced the development of TxA compared to untreated controls (intima proliferation of 23%±8% vs. 68%±7% [control]). 50mg/kg of MMF did not have any effect on the development of TxA. Strikingly, combination of Ganciclovir and low-dose MMF reduced the formation of TxA (intima proliferation of 27%±2% vs. 68%±7% [control]). The high-dose combination group (300mg MMF/72mg Ganciclovir) showed an intima proliferation of 24%±4%. FACS analysis of the spleen within this group revealed 12.73% CD4+cells with 14.70% CD4+CD25+FoxP3+cells. As compared to 17.5% CD4+cells with 11.1% CD4+CD25+FoxP3+cells in the control group. Single treatment with MMF (300mg) showed 10.55% CD4+ cells and 10.87% CD4+CD25+FoxP3+ cells within the analysed spleens. Conclusion: Our results demonstrate a dose-dependent positive effect of MMF on the development of TxA and a synergistic effect of Ganciclovir in combination with MMF.