Mycophenolate mofetil (MMF, RS-61443) inhibits inflammation and smooth muscle cell proliferation in rat aortic allografts

To investigate the impact of mycophenolate mofetil (MMF) on allograft arteriosclerosis (chronic rejection) in rat aortic allograft model, we administrated MMF 20 mg/kg/day from the day of transplantation and sacrificed the rats at 1-12 months afterwards. MMF significantly suppressed all major histological manifestations of allograft arteriosclerosis, i.e. adventitial inflammation, media necrosis and intimal thickening and cellularity. There was a significant decrease in the replication rate (3H-thymidine incorporation) of inflammatory cells in the adventitia and of smooth muscle cells (SMC) in the media. MMF did not have any major effect on mRNA expression of several growth factors, (determined by polymerase chain reaction with inbuilt glyceraldehyde-3-phosphate dehydrogenase control), which have previously been demonstrated to be elevated in nonimmunosuppressed allografts. Immunoperoxidase staining showed a 40% reduction in the number of adventitial interleukin-2 receptors expressing lymphoid cells in MMF-treated allografts. The intensity of SMC alpha-actin staining was also significantly reduced. As the results suggested that MMF may have a direct antiproliferative effect on SMC, this possibility was investigated in primary SMC cultures in vitro and using the carotid denudation model in vivo. Both approaches showed inhibition of SMC proliferation by MMF. Our results indicate that MMF inhibits histopathological changes of chronic rejection by reducing the immune response and possible replication of SMC.