A STAT3 inhibitor ameliorates CNS autoimmunity by restoring Teff:Treg balance.

Saba I Aqel,Xiaozhi Yang,Yuhong Yang,Emma E Kraus,Marissa F Farinas,Erin Y Zhao,Jinhua Song,Michael K Racke,Wei Pei,Amy E Lovett-Racke,Chenglong Li

doi:10.1172/jci.insight.142376

Abstract

Reestablishing an appropriate balance between T effector cells (Teff) and Tregs is essential for correcting autoimmunity. Multiple sclerosis (MS) is an immune-mediated chronic CNS disease characterized by neuroinflammation, demyelination, and neuronal degeneration, in which the Teff:Treg balance is skewed toward pathogenic Teffs Th1 and Th17 cells. STAT3 is a key regulator of Teff:Treg balance. Using the structure-based design, we have developed a potentially 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 that selective inhibition of STAT3 by the small molecule LLL12b recalibrates the effector and regulatory arms of CD4+ T responses, representing a potentially clinically translatable therapeutic strategy for MS.

Highlights

Multiple sclerosis (MS) is an immune-mediated CNS disease characterized by neuroinflammation, demyelination, and neuronal degeneration
We first determined whether STAT3 inhibition with LLL12 suppressed the development of myelin-specific Th17 cells and EAE progression (Supplemental Figure 2 and Supplemental Table 2)
Therapeutic administration of a small molecule STAT3 inhibitor prodrug LLL12b administered after EAE onset suppressed disease progression in adoptively transferred, chronic, and relapsing-remitting EAE, as well as EAE relapses when given during the remitting phase

Summary

Introduction

Multiple sclerosis (MS) is an immune-mediated CNS disease characterized by neuroinflammation, demyelination, and neuronal degeneration. MS affects over 1 million people in the United States [1]. Current disease-modifying therapies (DMTs) are not effective in all patients, and some of them are associated with significant risks, demonstrating an unmet clinical need for innovative therapies that correct the abnormalities underlying MS pathogenesis. Two subsets of myelin-specific CD4+ T effector cells (Teffs), Th1 and Th17 cells, mediate the formation of acute inflammatory lesions and disease progression in experimental autoimmune encephalomyelitis (EAE), a well-defined murine model of MS, and are implicated in MS pathogenesis. CD4+ Tregs have the potential to suppress encephalitogenic Teffs and the development of autoimmunity [2]. Teff:Treg balance is critical for normal immune function. Teff:Treg balance skewed toward Teffs favors autoimmunity, while therapeutically restoring Teff:Treg balance may lead to resolution of inflammation and amelioration of autoimmunity

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Results

Conclusion