A STAT3 inhibitor ameliorates CNS autoimmunity by restoring Teff:Treg Balance

摘要: Reestablishing an appropriate balance between T effector cells (Teff) and Tregs is essential for correcting autoimmunity. Multiple sclerosis (MS) immune-mediated chronic CNS disease characterized by neuroinflammation, demyelination, neuronal degeneration, in which the Teff:Treg skewed toward pathogenic Teffs Th1 Th17 cells. STAT3 a key regulator of balance. Using structure-based design, we have developed potentially novel small-molecule prodrug LLL12b that specifically inhibits suppresses differentiation expansion. Moreover, regulates fate decision inflammatory environment, shifting Th17:Treg favoring resolution inflammation. Therapeutic administration after onset significantly progression adoptively transferred, chronic, relapsing-remitting experimental autoimmune encephalomyelitis. Disease relapses were also suppressed given during remission phase. Additionally, shifts CD4+ from MS patients increases Teff sensitivity to Treg-mediated suppression. These data suggest selective inhibition small molecule recalibrates regulatory arms responses, representing clinically translatable therapeutic strategy MS.