Although Interferon-2 is one of the most popular treatments for multiple sclerosis, its mode of action as a drug is still not fully understood. Moreover, IFN-2 therapy is only partially effective and approximately 30% of MS patients do not respond to treatment. We recently published that response to IFN-2 therapy is dictated by TH1 and TH17 pathways. Using mouse models for MS, we found that IFN-2 attenuates TH1 induced disease but exacerbates TH17 disease. In a small cohort of MS patients, we observed high serum levels of IL-17F, a TH17 cytokine, in non-responders prior to the initiation of treatment. The goals of this research are to: 1. Determine the mechanisms by which IFN-2 treatment exerts its pro- and anti- inflammatory effects. This will be accomplished by using mouse models of MS and human CD4 T-cell culturing experiments, described in Aim 1 and 3 respectively. 2. Identify biomarkers in MS blood and spinal fluid that predict and track the responsiveness to IFN-2 treatment. This will be accomplished by analyzing cytokine profiles in patient's blood and spinal fluid in a longitudinal study, described in Aim 2. Training: The research proposed in this application covers a wide range of experimental techniques requiring expertise in animal models of autoimmunity, human immune cell biology, cell signaling, transcriptional regulation and experimentation with disease tissue. Therefore, additional training will be required in experimental techniques, statistical analysis, and organization of clinical research. Dr. Steinman, my mentor, along with Dr. Dunn (collaborator/consultant), and Dr. Racke (consultant) are experts in these areas and will ensure that these training needs are met. Environment: Stanford is a renowned academic research institute with a long record of producing cutting edge science. Stanford has a highly collaborative atmosphere with state-of- the-art facilities and world class investigators in many disciplines, many of whom are conducting research that is complementary to the work proposed in this application. The proposed research plan, training development and environment at Stanford will be highly conducive for my transition to an independent faculty. PUBLIC HEALTH RELEVANCE: Interferon-beta is the most popular treatment for multiple sclerosis. However, a major limitation with IFN-beta is that approximately 30% of MS patients do not respond to treatment. The major goal of this proposal is to determine the mode of action of IFN-beta therapy and identify biomarkers that can predict responsiveness to this treatment.