JAK inhibitor has the amelioration effect in lupus-prone mice: the involvement of IFN signature gene downregulation.

We previously reported that JAK/STAT pathway-mediated regulation of IRF-related genes may have an important role in the disease activity of SLE through analyzing the difference of gene expression in peripheral blood CD3+ T cells obtained from SLE patients. Recently pan-JAK inhibitor (JAKi) tofacitinib (TOFA) were developed and successfully applied to patients with rheumatoid arthritis. Therefore, the application possibility of TOFA was investigated for the new therapeutic strategy of SLE. Anti-dsDNA antibody and proteinuria were decreased and glomerulo/interstitial nephritis were ameliorated in any TOFA administered SLE mice. In splenic CD4+ T cell analysis, naïve cells significantly increased and effector/memory cells decreased. TOFA with dexamethasone (DEXA) therapy showed tendency to indicate stronger inhibitory effect comparing with TOFA or DEXA monotherapy. The gene expression of Ifit3/IFIT3 that related with anti-viral IFN signaling pathway was significantly suppressed in both CD4+ from SLE mice and CD3+ T cells from SLE patients after treatment. Both TOFA monotherapy and dual therapy with DEXA could suppress nephritis and modify immunological function in SLE mice with different genetic background. IFN signaling pathway was supposed to be important for the functional mechanism of TOFA to improve the disease condition. TOFA may contribute to the development of a new therapeutic strategy for SLE. The gene expression analysis was compared among tofacitinib, tofacitinib+dexamethsone, dexamethsone and non-treated control groups and extracted TOFA specific decreased genes in NZBWF1 mice.

我们此前通过分析系统性红斑狼疮（Systemic Lupus Erythematosus, SLE）患者外周血CD3+ T细胞的基因表达差异，报道了JAK/STAT通路（JAK/STAT pathway）介导的干扰素调节因子（Interferon Regulatory Factor, IRF）相关基因调控，可能在SLE的疾病活动度中发挥重要作用。近年来，泛JAK抑制剂（pan-JAK inhibitor, JAKi）托法替布（tofacitinib, TOFA）已被开发并成功应用于类风湿关节炎患者的治疗。因此，本研究探讨了托法替布应用于SLE新型治疗策略的可能性。给予托法替布治疗的SLE模型小鼠体内，抗双链DNA（anti-dsDNA）抗体与尿蛋白水平均出现下降，肾小球/间质性肾炎症状得到改善。对脾脏CD4+ T细胞的分析显示，初始T细胞比例显著升高，而效应/记忆T细胞比例降低。托法替布联合地塞米松（dexamethasone, DEXA）治疗相较于单一托法替布或单一地塞米松治疗，表现出更强的抑制趋势。经托法替布治疗后，SLE模型小鼠的CD4+ T细胞以及SLE患者的CD3+ T细胞中，与抗病毒干扰素信号通路相关的Ifit3/IFIT3基因表达均被显著抑制。无论托法替布单药治疗还是联合地塞米松的联合治疗，均可抑制不同遗传背景SLE模型小鼠的肾炎进展，并改善其免疫功能。干扰素信号通路被认为是托法替布改善SLE疾病状态的核心作用机制之一。托法替布有望为SLE的新型治疗策略开发提供助力。本研究对托法替布组、托法替布+地塞米松组、地塞米松组以及未处理对照组的基因表达谱进行了比较，从NZBWF1小鼠中筛选出了托法替布特异性下调的基因。