title: The effects of teriflunomide on lymphocyte subpopulations in human peripheral blood mononuclear cells in vitro.
abstract: 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.
authors.affiliation: BioInnovation Group, Sanofi, Cambridge, MA, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Jingchun
authors.initials: J
authors.lastname: Liu
authors.forename: Thomas
authors.initials: T
authors.lastname: Delohery
authors.forename: Donghui
authors.initials: D
authors.lastname: Zhang
authors.forename: Christopher
authors.initials: C
authors.lastname: Arendt
authors.forename: Catherine
authors.initials: C
authors.lastname: Jones
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D001402:B-Lymphocytes / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D003437:Crotonates / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006801:Humans; D006885:Hydroxybutyrates; D007155:Immunologic Factors / Q000494:pharmacology*; D016131:Lymphocyte Subsets / Q000187:drug effects*; D009570:Nitriles; D014052:Toluidines / Q000494:pharmacology*
chemical_list: D015703:Antigens, CD; D003437:Crotonates; D016207:Cytokines; D006885:Hydroxybutyrates; D007155:Immunologic Factors; D009570:Nitriles; D014052:Toluidines; C527525:teriflunomide
keywords: Anti-inflammatory; Anti-proliferative; CNS; De novo pyrimidine synthesis; Immunomodulation; Multiple sclerosis