Liu Qinghong, Xing Xiaoyan, He Jing
Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China.
Clin Exp Rheumatol. 2024 Dec;42(12):2437-2443. doi: 10.55563/clinexprheumatol/b91fx8. Epub 2024 Oct 29.
The Janus kinases-signal transducer and activator of transcription (JAK-STAT) signalling pathway plays a crucial role in autoimmunity and the signalling pathways of many cytokines in Sjögren's disease (SjD). Therefore, the aim of this study was to investigate both the therapeutic and immunomodulatory effects of the oral JAK3/JAK2/JAK1 inhibitor tofacitinib in a murine model of SjD.
Tofacitinib or vehicle was administered orally to the mice with SjD for 6 weeks. Salivary flow rate was measured every three weeks. Pathological changes of salivary gland were detected by haematoxylin-eosin staining, and the percentages of subsets of CD4+ T cells and B cells in the cervical lymph nodes (cLNs) and spleen was determined by flow cytometry.
Tofacitinib significantly ameliorated submandibular gland inflammation compared to the control group, as evidenced by reduced lymphocytic infiltration. Salivary flow rates improved significantly in tofacitinib treated mice compared to controls, indicating restored salivary gland function. The treatment also led to a substantial decrease in follicular helper T (Tfh) cells and the Tfh/Treg ratio in both the spleen and cLNs. Additionally, the frequencies of T helper 1 (Th1) and T helper 17 (Th17) cells were reduced in the spleen and cLNs.
Our data indicated that tofacitinib reduced percentages of effector T cells in an animal model of SjD. In addition, tofacitinib alleviated salivary gland inflammation and hypofunction, offering new insights into the clinical management of SjD.
Janus激酶-信号转导及转录激活因子（JAK-STAT）信号通路在自身免疫以及干燥综合征（SjD）中多种细胞因子的信号通路中起着关键作用。因此，本研究旨在探讨口服JAK3/JAK2/JAK1抑制剂托法替布在SjD小鼠模型中的治疗和免疫调节作用。
给患SjD的小鼠口服托法替布或赋形剂，持续6周。每3周测量唾液流速。通过苏木精-伊红染色检测唾液腺的病理变化，采用流式细胞术测定颈部淋巴结（cLNs）和脾脏中CD4+T细胞和B细胞亚群的百分比。
与对照组相比，托法替布显著改善了下颌下腺炎症，淋巴细胞浸润减少证明了这一点。与对照组相比，托法替布治疗的小鼠唾液流速显著提高，表明唾液腺功能恢复。该治疗还导致脾脏和cLNs中的滤泡辅助性T（Tfh）细胞以及Tfh/Treg比值大幅下降。此外，脾脏和cLNs中辅助性T细胞1（Th1）和辅助性T细胞17（Th17）的频率降低。
我们的数据表明，托法替布在SjD动物模型中降低了效应T细胞的百分比。此外，托法替布减轻了唾液腺炎症和功能减退，为SjD的临床管理提供了新的见解。
