title: Laquinimod, a quinoline-3-carboxamide, induces type II myeloid cells that modulate central nervous system autoimmunity.
abstract: Laquinimod is a novel oral drug that is currently being evaluated for the treatment of relapsing-remitting (RR) multiple sclerosis (MS). Using the animal model for multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), we examined how laquinimod promotes immune modulation. Oral laquinimod treatment reversed established RR-EAE and was associated with reduced central nervous system (CNS) inflammation, decreased Th1 and Th17 responses, and an increase in regulatory T cells (Treg). In vivo laquinimod treatment inhibited donor myelin-specific T cells from transferring EAE to naive recipient mice. In vivo laquinimod treatment altered subpopulations of myeloid antigen presenting cells (APC) that included a decrease in CD11c(+)CD11b(+)CD4(+) dendritic cells (DC) and an elevation of CD11b(hi)Gr1(hi) monocytes. CD11b(+) cells from these mice exhibited an anti-inflammatory type II phenotype characterized by reduced STAT1 phosphorylation, decreased production of IL-6, IL-12/23 and TNF, and increased IL-10. In adoptive transfer, donor type II monocytes from laquinimod-treated mice suppressed clinical and histologic disease in recipients with established EAE. As effects were observed in both APC and T cell compartments, we examined whether T cell immune modulation occurred as a direct effect of laquinimod on T cells, or as a consequence of altered APC function. Inhibition of Th1 and Th17 differentiation was observed only when type II monocytes or DC from laquinimod-treated mice were used as APC, regardless of whether myelin-specific T cells were obtained from laquinimod-treated or untreated mice. Thus, laquinimod modulates adaptive T cell immune responses via its effects on cells of the innate immune system, and may not influence T cells directly.
authors.affiliation: Department of Neurology and Program in Immunology, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Ulf
authors.initials: U
authors.lastname: Schulze-Topphoff
authors.forename: Aparna
authors.initials: A
authors.lastname: Shetty
authors.forename: Michel
authors.initials: M
authors.lastname: Varrin-Doyer
authors.forename: Nicolas
authors.initials: N
authors.lastname: Molnarfi
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Sagan
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Sobel
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Nelson
authors.forename: Scott S
authors.initials: SS
authors.lastname: Zamvil
mesh_terms: D000284:Administration, Oral; D019264:Adoptive Transfer; D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000628:therapy; D005260:Female; D007155:Immunologic Factors / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D022423:Myeloid Cells / Q000187:drug effects* / Q000276:immunology*; D015363:Quinolones / Q000008:administration & dosage / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology
chemical_list: D007155:Immunologic Factors; D015363:Quinolones; C476223:laquinimod