Department of Rheumatism and Immunology, Shenzhen Key Laboratory of Inflammatory and Immunology Diseases, Peking University Shenzhen Hospital, Shenzhen 518036, China.
Department of Pathology, Peking University Shenzhen Hospital, Shenzhen 518036, China.
Int J Mol Sci. 2022 Nov 2;23(21):13394. doi: 10.3390/ijms232113394.
Rheumatoid arthritis (RA) is a common disease worldwide and is treated commonly with methotrexate (MTX). CS12192 is a novel JAK3 inhibitor discovered by Chipscreen Biosciences for the treatment of autoimmune diseases. In the present study, we examined the therapeutic effect of CS12192 against RA and explored if the combinational therapy of CS12192 and MTX produced a synergistic effect against RA in rat collagen-induced arthritis (CIA). Arthritis was induced in male Sprague-Dawley rats by two intradermal injections of bovine type II collagen (CII) and treated with MTX, CS12192, or the combination of CS12192 and MTX daily for two weeks. Effects of different treatments on arthritis score, X-ray score, pathology, and expression of inflammatory cytokines and biomarkers were examined. We found that treatment with either CS12192 or MTX produced a comparable therapeutic effect on CIA including: (1) significantly lowering the arthritis score, X-ray score, serum levels of rheumatic factor (RF), C-reactive protein (CRP), and anti-nuclear antibodies (ANA); (2) largely alleviating histopathological damage, reducing infiltration of Th17 cells while promoting Treg cells; (3) inhibiting the expression of inflammatory cytokines and chemokines such as IL-1β, TNF-α, IL-6, CCL2, and CXCL1. All these inhibitory effects were further improved by the combinational therapy with MTX and CS12192. Of importance, the combinational treatment also resulted in a marked switching of the Th17 to Treg and the M1 to M2 immune responses in synovial tissues of CIA. Thus, when compared to the monotherapy, the combination treatment with CS12192 and MTX produces a better therapeutic effect against CIA with a greater suppressive effect on T cells and macrophage-mediated joint inflammation.
类风湿关节炎（RA）是一种常见的全球性疾病，通常采用甲氨蝶呤（MTX）治疗。CS12192 是由 Chipscreen Biosciences 发现的一种新型 JAK3 抑制剂，用于治疗自身免疫性疾病。在本研究中，我们研究了 CS12192 对 RA 的治疗作用，并探讨了 CS12192 与 MTX 联合治疗是否对胶原诱导性关节炎（CIA）大鼠具有协同作用。通过两次皮内注射牛 II 型胶原（CII）在雄性 Sprague-Dawley 大鼠中诱导关节炎，并每天用 MTX、CS12192 或 CS12192 和 MTX 的联合治疗治疗两周。检查了不同治疗方法对关节炎评分、X 射线评分、病理以及炎症细胞因子和生物标志物表达的影响。我们发现，CS12192 或 MTX 治疗对 CIA 均具有相当的治疗作用，包括：（1）显著降低关节炎评分、X 射线评分、血清类风湿因子（RF）、C 反应蛋白（CRP）和抗核抗体（ANA）水平；（2）显著减轻组织病理学损伤，减少 Th17 细胞浸润，同时促进 Treg 细胞；（3）抑制炎症细胞因子和趋化因子的表达，如 IL-1β、TNF-α、IL-6、CCL2 和 CXCL1。这些抑制作用通过 MTX 和 CS12192 的联合治疗进一步改善。重要的是，联合治疗还导致 CIA 滑膜组织中 Th17 向 Treg 和 M1 向 M2 免疫反应的明显转换。因此，与单药治疗相比，CS12192 和 MTX 的联合治疗对 CIA 具有更好的治疗效果，对 T 细胞和巨噬细胞介导的关节炎症具有更强的抑制作用。
