Department of Dermatology, Medical Faculty, Heinrich-Heine-University Düsseldorf, Moorenstr. 5, 40225, Düsseldorf, Germany.
Department and Hiller Research Unit for Rheumatology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
Arthritis Res Ther. 2021 May 21;23(1):144. doi: 10.1186/s13075-021-02509-8.
Tofacitinib is a novel Janus kinase (JAK) inhibitor approved for the treatment of rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis. In clinical trials, the most common adverse events observed were nasopharyngitis, upper respiratory tract infections, and zoster. JAKs are found downstream of the type II cytokine receptor family used by a number of T17 cell-associated cytokines for signal transduction. These cytokines lead to the secretion of antiviral and antimicrobial peptides (AMPs) by keratinocytes or synoviocytes. Blocking the JAK pathway might result in a diminished secretion of antimicrobial and antiviral peptides causing higher susceptibility to infections in patients treated with JAK inhibitors.
We treated primary human keratinocytes and synoviocytes with tofacitinib and subsequently added various cytokines and bacterial surface proteins before evaluation of the response via RT-qPCR. CD69 expression on tofacitinib-treated PBMCs was investigated via flow cytometry.
We found a markedly reduced gene expression of all tested antiviral peptides such as MX1 or ISG15 in keratinocytes and synoviocytes in the presence of tofacitinib in vitro. Additionally, we found that JAK inhibition reduced activation of T cells after stimulation with bacterial LPS or viral VZV gE.
The antiviral immunity is strongly inhibited in the presence of tofacitinib in vitro, while the antimicrobial immunity does not seem to be affected. In T cells, the overall activation process seems to be influenced by tofacitinib. These findings suggest that tofacitinib has an impact on antiviral immunity such as patients treated with tofacitinib often show adverse events like herpes zoster.
托法替尼是一种新型的 Janus 激酶（JAK）抑制剂，已被批准用于治疗类风湿关节炎、银屑病关节炎和溃疡性结肠炎。在临床试验中，观察到的最常见的不良事件是鼻咽炎、上呼吸道感染和带状疱疹。JAK 位于多种与 T17 细胞相关的细胞因子所使用的 II 型细胞因子受体家族的下游，用于信号转导。这些细胞因子导致角质形成细胞或滑膜细胞分泌抗病毒和抗菌肽（AMPs）。阻断 JAK 途径可能导致抗菌肽和抗病毒肽的分泌减少，从而使接受 JAK 抑制剂治疗的患者更容易感染。
我们用托法替尼处理原代人角质形成细胞和滑膜细胞，然后在评估 RT-qPCR 反应之前添加各种细胞因子和细菌表面蛋白。通过流式细胞术研究托法替尼处理的 PBMC 上的 CD69 表达。
我们发现，在体外存在托法替尼的情况下，所有测试的抗病毒肽，如 MX1 或 ISG15 的基因表达在角质形成细胞和滑膜细胞中明显降低。此外，我们发现 JAK 抑制减少了细菌 LPS 或病毒 VZV gE 刺激后 T 细胞的激活。
体外存在托法替尼时，抗病毒免疫受到强烈抑制，而抗菌免疫似乎不受影响。在 T 细胞中，整体激活过程似乎受到托法替尼的影响。这些发现表明，托法替尼对抗病毒免疫有影响，例如接受托法替尼治疗的患者经常出现疱疹性带状疱疹等不良反应。
