Autoimmune neurologic diseases

Oral

Modulating il-6/stat3 Signaling Pathway for Multiple Sclerosis Therapy

Thursday, June 15
5:45 PM - 7:00 PM

Multiple Sclerosis (MS) is an immune-mediated chronic CNS disease and IL-6/STAT3 pathway plays a critical role in MS pathogenesis. We have previously demonstrated that IL-6 induces the development of highly encephalitogenic Th17-cells. Meanwhile, IL-6/STAT3 pathway is a key signaling pathway blocking the development of inducible T-regulatory cells (iTreg); critical for dampening pathogenic inflammatory T-effector (Teff) responses. Therefore, dysregulated IL-6/STAT3 signaling skews Teff/Treg balance toward an enhanced Teff response; favoring the development of CNS autoimmunity. The dysregulation of IL-6/STAT3 signaling pathway has been observed in MS patients, suggesting IL-6/STAT3 signaling pathway may serve as an innovative target for reversing pathogenesis in patients. In support, both IL-6-/- and STAT3-/- mice are completely resistant to the EAE model of MS. Therefore, we developed small-molecule lead compounds targeting IL-6/STAT3 pathway. MDL-analogs bind to the D1 domain of GP130, preventing the IL-6/GP130 interaction; while LLL12-analogs bind to the SH2 domain of STAT3, preventing STAT3 phosphorylation. Both inhibit IL-6 induced IL-17 production in myelin-specific CD4 T-cells in a dose dependent manner without significant toxicity. Furthermore, adoptive transfer of LLL12 treated myelin-specific CD4 T-cells into naïve recipient mice leads to a significant reduction in EAE severity compared to control group, suggesting LLL12 analogs suppress the encephalitogenicity of myelin-specific CD4-T cells. More importantly, EAE mice treated with LLL12 analogs in vivo demonstrate reduced disease severity compared to control mice, suggesting LLL12 analog treatment in vivo suppresses EAE development. Together, our data suggest that these lead compounds have great potential to serve as an innovative therapy for MS.

Saba Aqel

Research Assistant
The Ohio State University Wexner Medical Center

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    Patrick Nuro-Gyina

    The Ohio State University Wexner Medical Center

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      Marissa Granitto

      The Ohio State University Wexner Medical Center

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        Yue Liu

        The Ohio State University Wexner Medical Center

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          Wei Pei

          The Ohio State University Wexner Medical Center

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            Amy Lovett-Racke

            The Ohio State University Wexner Medical Center

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              Michael Racke

              The Ohio State University Wexner Medical Center

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                Chenglong Li

                University of Florida Health Science Center

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                  Yuhong Yang

                  The ohio state university wexner medical center

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