The type I IFN pathway constrains Th17-mediated autoimmune diseases

Medical University Of South Carolina, Charleston SC

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Abstract

DESCRIPTION (provided by applicant): My goal in seeking a K22 Career Development Award is to make a successful transition from a postdoctoral fellow to an independent investigator. The long term goal of this grant application is to further elucidate the role of innate immune pathways in regulating Th17 cell differentiation and its associated autoimmune diseases. Recently, I discovered novel anti-inflammatory roles for IFN[unreadable] in regulating Th17 development and autoimmune diseases. Our data demonstrate that IFN[unreadable] induction and signaling pathways play critical roles in suppressing Th17-associated autoimmune and inflammatory diseases such as experimental autoimmune encephalomyelitis (EAE), an animal model of human MS. Our data also reveal that the beneficial effects of IFN-beta are likely through its ability to induce anti-inflammatory cytokines IL-10 and IL-27. I hypothesize that type I IFN induction plays a critical role in suppressing Th17-associated autoimmune and inflammatory diseases such as EAE. Specific Aim 1 will determine the regulatory role of Toll-like receptor (TLR) signaling pathways in promoting or suppressing EAE. Then Aim 2 will determine mechanisms responsible for IFN-beta-mediated inhibition of Th17 cell differentiation and EAE. Finally, I will explore how to modulate Th17-associated autoimmune and inflammatory diseases through activation of IFN-beta pathways as proposed in Aim 3. The K22 award will provide me with the opportunity to acquire additional training and to generate necessary data to launch an independent research program. Studies proposed in this application will not only elucidate how IFN-beta is effectively treating patients with multiple sclerosis, but also help to develop novel strategies to treat autoimmune and inflammatory diseases. The proposed studies in this K22 application will not only elucidate the physiological role of endogenous type I IFNs in inhibiting the development of autoimmune disease, but will also provide insight to understand how IFN[unreadable] works in the treatment of Multiple Sclerosis and to help design additional strategies to treat autoimmune and inflammatory disease.