ITK inhibitor BMS509744 ameliorates Collagen-Induced Arthritis via shifting the balance between Th17 and regulatory Th17 cells
作者单位：Sun Yat-sen University Penn State Univ Cornell Univ Univ of Tennessee
会议名称：《第十三届全国免疫学学术大会》
会议日期：2018年
学科分类：1002[医学-临床医学] 100201[医学-内科学(含：心血管病、血液病、呼吸系病、消化系病、内分泌与代谢病、肾病、风湿病、传染病)] 10[医学]
摘 要：Rheumatoid arthritis(RA) is a chronic inflammation disease that cannot be cured and current approaches have the severe side effects. Although the pathogenesis is not completely understood, many studies have suggested that the imbalance between Th17 cells/inflammatory cytokines and suppressive Foxp3 T regulatory cells(Tregs) is associated with the pathogenesis and development in RA progression. ITK is involved in signaling cascades mediating T-lymphocyte proliferation, differentiation, and migration and pro-inflammatory cytokine production. The small molecule BMS509744 covalently binds ITK and inhibits the kinase activity of ITK. Here we report that BMS509744 effectively Skewed Th cells to Treg under Th17 differentiation conditions and promote Treg induction under Treg differentiation condition, and give rise to increased Foxp3 expression across TCR doses under Th17 and Treg condition, these effects can be reversed by SGK1 inhibitor. Moreover, we found that Itk inhibitor decreased mTor activity and altered metabolic marker HIF1 a and SLC3 a which regulate the balance between Th17 and Treg cells. Additionally, BMS509744 effectively ameliorate collagen-induced arthritis in mice by shifting the Th17/Treg cell balance from Th17 predominance to Treg cell predominance. Our result indicates that BMS509744 is an effective RA therapeutic.