Bi Zhuajin, Zhang Qing, Gao Huajie, Ge Huizhen, Zhan Jiayang, Yang Mengge, Bu Bitao
Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.
Muscle Nerve. 2025 Mar;71(3):474-486. doi: 10.1002/mus.28348. Epub 2025 Jan 17.
INTRODUCTION/AIMS: Tofacitinib, a first-generation Janus kinase (JAK) 1/3 inhibitor, is commonly used for treating ulcerative colitis and rheumatoid arthritis. However, its role in myasthenia gravis (MG) remains unclear. This study aimed to evaluate the immunomodulatory effects of tofacitinib on experimental autoimmune myasthenia gravis (EAMG) and peripheral blood mononuclear cells (PBMCs) from patients with MG.
Flow cytometry, enzyme-linked immunosorbent assay (ELISA), quantitative reverse transcription polymerase chain reaction (qRT-PCR), and Western blot were used to evaluate the effects of tofacitinib on T helper (Th) cell profiles, humoral immune responses, and the JAK-signal transducer and activator of transcription (STAT) pathway proteins.
In vivo, tofacitinib significantly ameliorated EAMG severity in rats, reducing the proportions of Th1, Th17 and memory B cells, and anti-acetylcholine receptor (AChR) antibodies levels, while increasing the proportions of regulatory T (Treg) cells. In vitro, tofacitinib administration resulted in a significant decrease in the proportions of Th1 and IgG-secreting B cell, and a significant upregulation of Treg cells in mononuclear cells (MNCs) from EAMG rats, which was consistent with findings in PBMCs from MG patients. Further analysis revealed that tofacitinib inhibited CD4 T cell differentiation into Th1 by decreasing phosphorylated STAT1 levels, while promoting Treg differentiation via increased phosphorylated STAT5 levels in MNCs from EAMG rats.
Tofacitinib modulates Th cell profiles and humoral immune responses by targeting the JAK-STAT pathway, suggesting its potential as a therapeutic candidate for MG. Further clinical studies are warranted to evaluate the efficacy and safety of tofacitinib in MG patients.
引言/目的：托法替布是第一代 Janus 激酶（JAK）1/3 抑制剂，常用于治疗溃疡性结肠炎和类风湿性关节炎。然而，其在重症肌无力（MG）中的作用仍不清楚。本研究旨在评估托法替布对实验性自身免疫性重症肌无力（EAMG）以及 MG 患者外周血单个核细胞（PBMC）的免疫调节作用。
采用流式细胞术、酶联免疫吸附测定（ELISA）、定量逆转录聚合酶链反应（qRT-PCR）和蛋白质印迹法，评估托法替布对辅助性 T（Th）细胞谱、体液免疫反应以及 JAK-信号转导和转录激活因子（STAT）通路蛋白的影响。
在体内，托法替布显著改善了大鼠 EAMG 的严重程度，降低了 Th1、Th17 和记忆 B 细胞的比例以及抗乙酰胆碱受体（AChR）抗体水平，同时增加了调节性 T（Treg）细胞的比例。在体外，给予托法替布导致 EAMG 大鼠单核细胞（MNC）中 Th1 和分泌 IgG 的 B 细胞比例显著降低，Treg 细胞显著上调，这与 MG 患者 PBMC 中的结果一致。进一步分析表明，托法替布通过降低 EAMG 大鼠 MNC 中磷酸化 STAT1 水平抑制 CD4 T 细胞向 Th1 分化，同时通过增加磷酸化 STAT5 水平促进 Treg 分化。
托法替布通过靶向 JAK-STAT 通路调节 Th 细胞谱和体液免疫反应，表明其作为 MG 治疗候选药物的潜力。有必要进行进一步的临床研究以评估托法替布在 MG 患者中的疗效和安全性。
