ResearchIn-Press PreviewTherapeutics
Open Access | 10.1172/jci.insight.142376
1Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, United States of America
2Department of Medicinal Chemistry, University of Florida, Gainesville, United States of America
3Neuroscience Program, The Ohio State University College of Arts and Sciences, Columbus, United States of America
4Department of Microbial Infection and Immunity, The Ohio State University Wexner Medical Center, Columbus, United States of America
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1Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, United States of America
2Department of Medicinal Chemistry, University of Florida, Gainesville, United States of America
3Neuroscience Program, The Ohio State University College of Arts and Sciences, Columbus, United States of America
4Department of Microbial Infection and Immunity, The Ohio State University Wexner Medical Center, Columbus, United States of America
Find articles by Yang, X. in: JCI | PubMed | Google Scholar
1Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, United States of America
2Department of Medicinal Chemistry, University of Florida, Gainesville, United States of America
3Neuroscience Program, The Ohio State University College of Arts and Sciences, Columbus, United States of America
4Department of Microbial Infection and Immunity, The Ohio State University Wexner Medical Center, Columbus, United States of America
Find articles by Kraus, E. in: JCI | PubMed | Google Scholar
1Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, United States of America
2Department of Medicinal Chemistry, University of Florida, Gainesville, United States of America
3Neuroscience Program, The Ohio State University College of Arts and Sciences, Columbus, United States of America
4Department of Microbial Infection and Immunity, The Ohio State University Wexner Medical Center, Columbus, United States of America
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1Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, United States of America
2Department of Medicinal Chemistry, University of Florida, Gainesville, United States of America
3Neuroscience Program, The Ohio State University College of Arts and Sciences, Columbus, United States of America
4Department of Microbial Infection and Immunity, The Ohio State University Wexner Medical Center, Columbus, United States of America
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1Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, United States of America
2Department of Medicinal Chemistry, University of Florida, Gainesville, United States of America
3Neuroscience Program, The Ohio State University College of Arts and Sciences, Columbus, United States of America
4Department of Microbial Infection and Immunity, The Ohio State University Wexner Medical Center, Columbus, United States of America
Find articles by Zhao, E. in: JCI | PubMed | Google Scholar
1Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, United States of America
2Department of Medicinal Chemistry, University of Florida, Gainesville, United States of America
3Neuroscience Program, The Ohio State University College of Arts and Sciences, Columbus, United States of America
4Department of Microbial Infection and Immunity, The Ohio State University Wexner Medical Center, Columbus, United States of America
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1Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, United States of America
2Department of Medicinal Chemistry, University of Florida, Gainesville, United States of America
3Neuroscience Program, The Ohio State University College of Arts and Sciences, Columbus, United States of America
4Department of Microbial Infection and Immunity, The Ohio State University Wexner Medical Center, Columbus, United States of America
Find articles by Lovett-Racke, A. in: JCI | PubMed | Google Scholar
1Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, United States of America
2Department of Medicinal Chemistry, University of Florida, Gainesville, United States of America
3Neuroscience Program, The Ohio State University College of Arts and Sciences, Columbus, United States of America
4Department of Microbial Infection and Immunity, The Ohio State University Wexner Medical Center, Columbus, United States of America
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1Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, United States of America
2Department of Medicinal Chemistry, University of Florida, Gainesville, United States of America
3Neuroscience Program, The Ohio State University College of Arts and Sciences, Columbus, United States of America
4Department of Microbial Infection and Immunity, The Ohio State University Wexner Medical Center, Columbus, United States of America
Find articles by Li, C. in: JCI | PubMed | Google Scholar
1Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, United States of America
2Department of Medicinal Chemistry, University of Florida, Gainesville, United States of America
3Neuroscience Program, The Ohio State University College of Arts and Sciences, Columbus, United States of America
4Department of Microbial Infection and Immunity, The Ohio State University Wexner Medical Center, Columbus, United States of America
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Published January 7, 2021 - More info
Reestablishing an appropriate balance between T effector cells (Teff) and T regulatory cells (Treg) is essential for correcting autoimmunity. Multiple Sclerosis (MS) is an immune-mediated chronic central nervous system (CNS) disease characterized by neuroinflammation, demyelination, and neuronal degeneration, in which the Teff:Treg balance is skewed toward pathogenic Teff cells, Th1 and Th17 cells. Signal transducer and activator of transcription 3 (STAT3) is a key regulator of Teff:Treg balance. Using the structure-based design, we have developed a novel small-molecule prodrug LLL12b that specifically inhibits STAT3 and suppresses Th17 differentiation and expansion. Moreover, LLL12b regulates the fate decision between Th17 and Tregs in an inflammatory environment, shifting Th17:Treg balance toward Tregs and favoring the resolution of inflammation. Therapeutic administration of LLL12b after disease onset significantly suppresses disease progression in adoptively transferred, chronic, and relapsing-remitting experimental autoimmune encephalomyelitis. Disease relapses were also significantly suppressed by LLL12b given during the remission phase. Additionally, LLL12b shifts Th17:Treg balance of CD4 T cells from MS patients toward Tregs and increases Teff sensitivity to Treg-mediated suppression. These data suggest selective inhibition of STAT3 by the novel small molecule LLL12b recalibrates the effector and regulatory arms of CD4 T responses, representing a potentially clinically translatable therapeutic strategy for MS.