title: Amelioration of experimental autoimmune encephalomyelitis by the quinoline-3-carboxamide paquinimod: reduced priming of proinflammatory effector CD4(+) T cells.
abstract: Quinoline-3-carboxamide compounds (Q compounds) have demonstrated efficacy in treating autoimmune disease in both humans and mice. However, the mode of action of these compounds is poorly understood. Here, we show that preventive treatment with the Q compound paquinimod (ABR-215757) during the first 5 days after induction of experimental autoimmune encephalomyelitis is sufficient to significantly ameliorate disease symptoms. Parallel cell-depletion experiments demonstrated that Ly6C(hi) inflammatory monocytes play an essential role in this phase. The paquinimod-induced amelioration correlated with reduced priming of antigen-specific CD4(+) T cells and reduced frequency of IFN-γ- and IL-17-producing cells in draining lymph nodes. Importantly, the treatment did not inhibit T-cell division per se. In mice with established experimental autoimmune encephalomyelitis, the numbers of Ly6C(hi) CD115(+) inflammatory monocytes and CD11b(+)CD11c(+) dendritic cells (DCs) were reduced in spleen, but not in bone marrow or draining lymph nodes of treated mice. Inflammatory monocyte-derived DCs and CD4(+) T cells were also reduced in the brain. In contrast, there was no decrease in DC subsets previously shown to be critical for effector CD4(+) T-cell development in lymph nodes. Taken together, these data indicate that preventive treatment with paquinimod ameliorates experimental autoimmune encephalomyelitis by reducing effector T-cell priming and, on prolonged treatment, displays a selective effect by decreasing distinct subpopulations of splenic CD11b(+) myeloid cells.
authors.affiliation: Immunology Group, Section for Immunology, Department of Experimental Medical Science, Faculty of Medicine, Lund University, Lund, Sweden.
authors.forename: Sofia
authors.initials: S
authors.lastname: Helmersson
authors.forename: Anette
authors.initials: A
authors.lastname: Sundstedt
authors.forename: Adnan
authors.initials: A
authors.lastname: Deronic
authors.forename: Tomas
authors.initials: T
authors.lastname: Leanderson
authors.forename: Fredrik
authors.initials: F
authors.lastname: Ivars
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology; D039481:CD11b Antigen / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D002490:Central Nervous System / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D045142:Cross-Priming / Q000187:drug effects / Q000276:immunology*; D003713:Dendritic Cells / Q000187:drug effects / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D007156:Immunologic Memory / Q000187:drug effects; D007249:Inflammation / Q000276:immunology / Q000473:pathology*; D007371:Interferon-gamma / Q000096:biosynthesis; D020381:Interleukin-17 / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use*; D013154:Spleen / Q000473:pathology
chemical_list: D039481:CD11b Antigen; D020381:Interleukin-17; D011804:Quinolines; C541322:quinoline-3-carboxamide; D007371:Interferon-gamma; C573440:paquinimod