Department of Medical Parasitology & Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland.
University of Basel, Basel, Switzerland.
PLoS Pathog. 2020 Feb 18;16(2):e1008312. doi: 10.1371/journal.ppat.1008312. eCollection 2020 Feb.
TNF-α- as well as non-TNF-α-targeting biologics are prescribed to treat a variety of immune-mediated inflammatory disorders. The well-documented risk of tuberculosis progression associated with anti-TNF-α treatment highlighted the central role of TNF-α for the maintenance of protective immunity, although the rate of tuberculosis detected among patients varies with the nature of the drug. Using a human, in-vitro granuloma model, we reproduce the increased reactivation rate of tuberculosis following exposure to Adalimumab compared to Etanercept, two TNF-α-neutralizing biologics. We show that Adalimumab, because of its bivalence, specifically induces TGF-β1-dependent Mycobacterium tuberculosis (Mtb) resuscitation which can be prevented by concomitant TGF-β1 neutralization. Moreover, our data suggest an additional role of lymphotoxin-α-neutralized by Etanercept but not Adalimumab-in the control of latent tuberculosis infection. Furthermore, we show that, while Secukinumab, an anti-IL-17A antibody, does not revert Mtb dormancy, the anti-IL-12-p40 antibody Ustekinumab and the recombinant IL-1RA Anakinra promote Mtb resuscitation, in line with the importance of these pathways in tuberculosis immunity.
TNF-α 以及非 TNF-α 靶向生物制剂被用于治疗多种免疫介导的炎症性疾病。抗 TNF-α 治疗与结核进展风险的明确关联突出了 TNF-α 在维持保护性免疫中的核心作用，尽管在接受不同药物治疗的患者中，结核的检出率有所不同。我们使用体外肉芽肿模型重现了与依那西普相比，阿达木单抗治疗后结核分枝杆菌（Mycobacterium tuberculosis，Mtb）再激活率增加的现象。我们表明，由于阿达木单抗的双价性，它可特异性地诱导 TGF-β1 依赖性 Mtb 复苏，而同时中和 TGF-β1 可以预防这种复苏。此外，我们的数据表明，依那西普中和的淋巴毒素-α 可能在控制潜伏性结核感染方面具有额外作用，但阿达木单抗则没有。此外，我们发现，虽然抗 IL-17A 抗体司库珠单抗不能逆转 Mtb 休眠，但抗 IL-12-p40 抗体乌司奴单抗和重组 IL-1RA 阿那白滞素可促进 Mtb 复苏，这与这些途径在结核病免疫中的重要性一致。
