Laquinimod suppresses CNS autoimmunity by activation of natural killer cells (P1.161)

OBJECTIVE: This study investigated the effects of laquinimod on NK cells in MOG35-55 immunized C57BL/6 mice. BACKGROUND: Laquinimod, a new orally active immunomodulator, considerably reduced disability progression and brain atrophy in relapsing-remitting MS patients. In animal models for MS, LAQ decreased the immunogenicity of dendritic cells (DCs) and induced type II myeloid cells. Since recent immunological studies emphasized a strong crosstalk between DCs and natural killer cells (NKs), we analyzed whether LAQ modulates NK cell responses. METHODS: NK cells of LAQ-treated, MOG35-55 immunized animals were characterized by flow cytometry and functional studies with ex vivo purified NK cells were performed. In addition, treatment effects of LAQ were analyzed in EAE animals depleted of NK cells by PK136 antibody administration. RESULTS: LAQ increased the percentage of CD69+ NK cells (p < 0.001) and upregulated the expression of the activating receptors TACTILE (p < 0.001), DNAM-1 (p<0.01) and NKG2D (p < 0.001) specifically on NK cells. LAQ mediated NK cell activation significantly improved the killing of B16F10 melanoma cells and the production of cytokines in response to IL-12 and IL-18 stimulation in vitro. In a triple co-culture system with 2D2 T cells and bone marrow derived DCs, NK cells derived from LAQ-treated mice significantly inhibited T cell proliferation in response to MOG35-55 (p<0.05). This inhibitory effect depended on direct cell-cell contact between NK cells and DCs and required the presence of the poliovirus receptor (CD155) on DCs. Depletion of NK cells in vivo did not change the LAQ-induced reduction of DCs (CD11chigh MHCII+) in the spleen but impaired the efficacy to suppress EAE. CONCLUSIONS:Treatment with LAQ induced NK cell activation, which contributes to the efficacy of LAQ to suppress CNS autoimmunity. In MS, NK cell functions are impaired and LAQ might restore NK cell function. Study Supported by: Teva Pharmaceutical Industries Ltd. Disclosure: Dr. Nessler has received research support from Teva Neuroscience. Dr. Ott has received research support from Teva Neuroscience. Dr. Wegner has received research support from Teva Neuroscience. Dr. Hayardeny has nothing to disclose. Dr. Ullrich has nothing to disclose. Dr. Brueck has received personal compensation for activities with Novartis Pharma, Biogen Idec, Bayer Vital, Genzyme, Merck Serono, and Teva Pharma.