Laquinimod, a Quinoline-3-Carboxamide, Induces Type II Myeloid Cells That Modulate Central Nervous System AutoimmunityReportar como inadecuado

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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 CD11bhiGr1hi 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.

Autor: Ulf Schulze-Topphoff , Aparna Shetty , Michel Varrin-Doyer, Nicolas Molnarfi, Sharon A. Sagan, Raymond A. Sobel, Patricia A. Nels



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