Lymphocyte modulation by tofacitinib in patients with rheumatoid arthritis
Lymphocyte modulation by tofacitinib in patients with rheumatoid arthritis
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DOI：
10.1111/cei.13609
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发表时间：
2021-05-28
影响因子：
4.6
通讯作者：
De Santis, Maria
中科院分区：
文献类型：
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作者：
Isailovic, Natasa;Ceribelli, Angela;De Santis, Maria
Tofacitinib是一种口服小分子药物，靶向细胞内Janus激酶信号传导和转录激活因子（JAK-STAT）通路，已被批准用于治疗活动性类风湿关节炎（RA）。我们研究了托法替尼对RA淋巴细胞对B和T细胞胶原表位的反应的影响，这些表位是天然的和翻译后修饰的。特别地，用II型胶原肽（T261-273、B359-369、carT261-273、citB359-369）或肉芽酸酯phorbol acetate (PMA)/离子霉素/CD40L在存在或不存在100 nM tofacitinib的情况下培养20小时，用荧光活化细胞分选仪（FACS）分析RA患者和健康人的外周血单个核细胞（PBMCs）。不含brefeldin A的培养液用于细胞因子上清酶联免疫吸附试验（ELISA）分析。托法替尼通过刺激B[白细胞介素(IL)-6和肿瘤坏死因子(TNF)- α]和T[干扰素(IFN)- γ， IL-17或TNF- α]细胞在短期内下调炎症细胞因子，同时也观察到外周血单核细胞（PBMC）上清中IL-17和IL-6水平显著降低。IL-10在RA患者胶原刺激的B细胞中显著降低，而在对照组中升高，从而反映了RA患者对胶原自身表位的改变反应。托法替尼部分阻止胶原表位刺激的RA B细胞IL-10下调。综上所述，托法替尼在胶原表位刺激下对RA患者的B细胞有快速调节作用，但不减少淋巴细胞产生炎症细胞因子。
Tofacitinib is an oral small molecule targeting the intracellular Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathways approved for the treatment of active rheumatoid arthritis (RA). We investigated the effects of tofacitinib on the response of RA lymphocytes to B and T cell collagen epitopes in their native and post-translationally modified forms. In particular, peripheral blood mononuclear cells (PBMCs) from patients with RA and healthy subjects were cultured with type II collagen peptides (T261-273, B359-369, carT261-273, citB359-369) or with phorbol myristate acetate (PMA)/ionomycin/CD40L in the presence or absence of 100 nM tofacitinib for 20 h and analyzed by fluorescence activated cell sorter (FACS). Cultures without brefeldin A were used for cytokine supernatant enzyme-linked immunosorbent assay (ELISA) analysis. Tofacitinib down-regulated inflammatory cytokines by stimulated B [interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha] and T [interferon (IFN)-gamma, IL-17 or TNF-alpha] cells in the short term, while a significant reduction of IL-17 and IL-6 levels in peripheral blood mononuclear cell (PBMC) supernatant was also observed. IL-10 was significantly reduced in collagen-stimulated B cells from patients with RA and increased in controls, thus mirroring an altered response to collagen self-epitopes in RA. Tofacitinib partially prevented the IL-10 down-modulation in RA B cells stimulated with collagen epitopes. In conclusion, the use of tofacitinib exerts a rapid regulatory effect on B cells from patients with RA following stimulation with collagen epitopes while not reducing inflammatory cytokine production by lymphocytes.