Laquinimod Promotes T Cell Immune Modulation in Central Nervous System Autoimmunity Via Type II (M2) Myeloid APC (P02.105)

Abstract

Objective: We investigated whether T cell immune modulation by laquinimod was mediated through its effects on myeloid antigen presenting cells (APC) or directly on T cells. Background Laquinimod is a novel oral drug that is being evaluated for treatment of RR multiple sclerosis (MS). In the MS model, EAE, laquinimod has been shown to reduce CNS infiltration and demyelination, as well as promote T cell immune modulation. Design/Methods: The effect on the function of myeloid APC was tested by using in vivo laquinimod-treated cells as APC for meylin-specific T cells and by transferring laquinimod treated APC into mice with established EAE. Results: Oral laquinimod treatment reversed established RR-EAE, and was associated with reduced 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 and an elevation of CD11bhiGr1hi monocytes. CD11b+ cells from these mice exhibited anti-inflammatory type II (M2) phenotype characterized by reduced STAT1 phosphorylation, decreased production of IL-6, IL-12/23 and TNF, and increased IL-10. In adoptive transfer, these donor type II monocytes suppressed clinical and histologic signs in recipients with established EAE. We examined whether T cell immune modulation occurred as a direct effect of laquinimod, or as a consequence of altered APC function. Inhibition of Th1 and Th17 differentiation was observed only when type II monocytes from laquinimod-treated mice were used as APC, regardless of whether myelin-specific T cells were obtained from laquinimod-treated or untreated mice. Conclusions: Our results show that Laquinimod does not act directly on T cells, but modulates adaptive T cell immune responses via its effect on myeloid APC. Supported by: Support was provided to S.S.Z. by NIH (RO1 AI073737 and NS063008), the NMSS (RG 4124), Teva Pharmaceuticals, and the Maisin Foundation. Disclosure: Dr. Schulze Topphoff has nothing to disclose. Dr. Shetty has received research support from Boehringer Ingelheim. Dr. Varrin-Doyer has nothing to disclose. Dr. Molnarfi has nothing to disclose. Dr. Sagan has received research support from the Guthy Jackson Charitable Foundation. Dr. Sobel has received research support from the NIH. Dr. Nelson has nothing to disclose. Dr. Zamvil has received personal compensation for activities with Biogen Idec, Teva Neuroscience and EMD Serono-Pfizer. Dr. Zamvil has received research support from the National Institutes of Health, National Multiple Sclerosis Society, the Maisin Foundation, the Guthy Jackson Charitable Foundation, Teva Neuroscience, and Boehringer Ingelheim Pharmaceuticals, Inc.