Byng-Maddick Rachel, Turner Carolin T, Pollara Gabriele, Ellis Matthew, Guppy Naomi J, Bell Lucy C K, Ehrenstein Michael R, Noursadeghi Mahdad
Division of Infection and Immunity, University College London, London, United Kingdom.
Division of Medicine, University College London, London, United Kingdom.
Front Immunol. 2017 Aug 4;8:932. doi: 10.3389/fimmu.2017.00932. eCollection 2017.
The impact of anti-tumor necrosis factor (TNF) therapies on inducible TNF-dependent activity in humans has never been evaluated . We aimed to test the hypothesis that patients responding to anti-TNF treatments exhibit attenuated TNF-dependent immune responses at the site of an immune challenge. We developed and validated four context-specific TNF-inducible transcriptional signatures to quantify TNF bioactivity in transcriptomic data. In anti-TNF treated rheumatoid arthritis (RA) patients, we measured the expression of these biosignatures in blood, and in skin biopsies from the site of tuberculin skin tests (TSTs) as a human experimental model of multivariate cell-mediated immune responses. In blood, anti-TNF therapies attenuated TNF bioactivity following stimulation. However, at the site of the TST, TNF-inducible gene expression and genome-wide transcriptional changes associated with cell-mediated immune responses were comparable to that of RA patients receiving methotrexate only. These data demonstrate that anti-TNF agents in RA patients do not inhibit inducible TNF activity at the site of an acute inflammatory challenge , as modeled by the TST. We hypothesize instead that their therapeutic effects are limited to regulating TNF activity in chronic inflammation or by alternative non-canonical pathways.
抗肿瘤坏死因子（TNF）疗法对人类诱导性TNF依赖性活性的影响从未得到评估。我们旨在验证这一假设：对抗TNF治疗有反应的患者在免疫激发部位表现出减弱的TNF依赖性免疫反应。我们开发并验证了四种特定背景下的TNF诱导转录特征，以量化转录组数据中的TNF生物活性。在接受抗TNF治疗的类风湿性关节炎（RA）患者中，我们测量了这些生物特征在血液中的表达，以及在结核菌素皮肤试验（TST）部位的皮肤活检中的表达，TST作为多变量细胞介导免疫反应的人体实验模型。在血液中，抗TNF疗法在刺激后减弱了TNF生物活性。然而，在TST部位，与细胞介导免疫反应相关的TNF诱导基因表达和全基因组转录变化与仅接受甲氨蝶呤治疗的RA患者相当。这些数据表明，RA患者中的抗TNF药物在TST所模拟的急性炎症激发部位不会抑制诱导性TNF活性。相反，我们推测它们的治疗效果仅限于调节慢性炎症中的TNF活性或通过替代的非经典途径。
