Tumor Necrosis Factor (TNF) Bioactivity at the Site of an Acute Cell-Mediated Immune Response Is Preserved in Rheumatoid Arthritis Patients Responding to Anti-TNF Therapy.
Tumor Necrosis Factor (TNF) Bioactivity at the Site of an Acute Cell-Mediated Immune Response Is Preserved in Rheumatoid Arthritis Patients Responding to Anti-TNF Therapy.
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DOI：
10.3389/fimmu.2017.00932
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发表时间：
2017
影响因子：
7.3
通讯作者：
Noursadeghi M
中科院分区：
文献类型：
--
作者：
Byng-Maddick R;Turner CT;Pollara G;Ellis M;Guppy NJ;Bell LCK;Ehrenstein MR;Noursadeghi M
从未在体内评估抗肿瘤坏死因子（TNF）疗法对人类诱导型TNF依赖性活性的影响。我们旨在检验以下假设：对抗TNF治疗的患者在免疫攻击部位表现出减弱的TNF依赖性免疫反应。我们开发并验证了四个特定于上下文特异性TNF诱导的转录特征，以量化转录组数据中的TNF生物活性。在抗TNF治疗的类风湿关节炎（RA）患者中，我们测量了血液中这些生物签名的表达，以及来自结核蛋白皮肤测试部位（TSTS）的皮肤活检中的表达，作为多元细胞细胞介导的免疫反应的人类实验模型。在血液中，抗TNF疗法在体内刺激后减弱了TNF生物活性。但是，在TST的位置，与细胞介导的免疫反应相关的TNF诱导基因表达和全基因组的转录变化与仅接受甲氨蝶呤的RA患者相当。这些数据表明，RA患者的抗TNF药物不会抑制由TST建模的体内急性炎症挑战部位的诱导型TNF活性。我们假设它们的治疗作用仅限于调节慢性炎症或替代性非经典途径中的TNF活性。
The impact of anti-tumor necrosis factor (TNF) therapies on inducible TNF-dependent activity in humans has never been evaluated in vivo. 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 ex vivo 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 in vivo, 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.
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DOI：
10.1038/nrrheum.2015.169
发表时间：
2016-01
期刊：
Nature reviews. Rheumatology
影响因子：
--
作者：
Kalliolias GD;Ivashkiv LB
通讯作者：
Ivashkiv LB
影响因子：
4.9
作者：
Marotte H;Maslinski W;Miossec P
通讯作者：
Miossec P
影响因子：
4.4
作者：
Botha, T;Ryffel, B
通讯作者：
Ryffel, B
影响因子：
15.9
作者：
Bruns, Heiko;Meinken, Christoph;Stenger, Steffen
通讯作者：
Stenger, Steffen
影响因子：
11.4
作者：
KEFFER, J;PROBERT, L;KOLLIAS, G
通讯作者：
KOLLIAS, G