Antidiabetogenic effect of mycophenolate mofetil is associated with down-regulation of adhesive interactions and autoreactive cell activation

Abstract

We have investigated the immunomodulatory potential of mycophenolate mofetil (MMF) on the development of autoimmune diabetes induced by multiple low doses of streptozotocin (MLD-SZ) in genetically susceptible DA rats. Administration of 25 mg/kg MMF continuously during the 7 weeks of MLD-SZ treatment, or as a 10-day treatment starting together with MLD-SZ (early treatment), or 5 days after the last dose of SZ (late treatment) significantly suppressed the development of hyperglycemia. Ex vivo analyses performed on day 10 after diabetes induction showed that MMF treatment downregulates adhesive interactions and proliferation of autoreactive spleen cells. Similar effects were observed in vitro when MLD-SZ-derived splenocytes were cultured with an active metabolite of MMF, mycophenolic acid (MPA). These results suggest that the antidiabetogenic effect of MMF involves inhibition of the expansion and migration of autoreactive cells.