Analysis of Laquinimod Efficiency during Experimental Autoimmune Encephalomyelitis (P02.115)

Objective: The study aims to investigate the cellular mode of action of laquinimod in experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis. Background Laquinimod is an orally administered CNS-active immunomodulator. Phase III data in RRMS patients indicate a positive effects of laquinimod 0.6 mg on clinical disease activity as evidenced by slowing the progression of disability, reducing the rate of MRI-measured brain volume loss and reducing relapse rates, all coupled with a favorable safety and tolerability profile. In EAE, it has been shown that laquinimod acts on autoaggressive T cells by reducing proinflammatory Th1 cytokine production. However, the exact cellular and molecular mechanisms of laquinimod are still incompletely understood. Design/Methods: In this study we set out to test the efficacy of laquinimod in both preventive (application of laquinimod for 14 days starting at the time of immunization) and therapeutic (starting the treatment when first symptoms occurred for 7 days) regimens in the MOG 35-55 -induced murine EAE model. Using intravital two photon microscopy combined with molecular ex vivo -analyses we are currently evaluating the locomotion and function of pathogenic effector T cells during the different phases of EAE as well as their interaction with other immune cells. Results: Our preliminary results show that laquinimod is able to ameliorate EAE in a dose-dependent manner in MOG-induced C57Bl/6 EAE as well as in a more aggressive and fulminant model using transfer of transgenic MOG-specific T cells. This was observed both in the preventive and therapeutic setting. Furthermore, we observed reduced proliferation of MOG-specific T cells and a reduction in the expression of activation markers in the priming phase and later a reduced production of pro-inflammatory cytokines such as IFN-gamma and IL17. Conclusions: In our experimental model used, laquinimod was shown to act early on antigen-specific T cells in the priming/preclinical phase before symptoms start to occur. Supported by: TEVA. Disclosure: Dr. Luhder has received research support from Teva. Dr. Winchenbach has nothing to disclose. Dr. Flugel has received research support from Teva.