Teriflunomide is an inhibitor of dihydro-orotate dehydrogenase (DHODH), and is hypothesized to ameliorate multiple sclerosis by reducing proliferation of stimulated lymphocytes. We investigated teriflunomide's effects on proliferation, activation, survival, and function of stimulated human peripheral blood mononuclear cell subsets in vitro. Teriflunomide had little/no impact on lymphocyte activation but exerted significant dose-dependent inhibition of T- and B-cell proliferation, which was uridine-reversible (DHODH-dependent). Viability analyses showed no teriflunomide-associated cytotoxicity. Teriflunomide significantly decreased release of several pro-inflammatory cytokines from activated monocytes in a DHODH-independent fashion. In conclusion, teriflunomide acts on multiple immune cell types and processes via DHODH-dependent and independent mechanisms.
Keywords: Anti-inflammatory; Anti-proliferative; CNS; De novo pyrimidine synthesis; Immunomodulation; Multiple sclerosis.