Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, USA.
J Immunol. 2012 Apr 1;188(7):3169-78. doi: 10.4049/jimmunol.1103298. Epub 2012 Feb 29.
Increased rates of tuberculosis (TB) reactivation have been reported in humans treated with TNF-α (TNF)-neutralizing drugs, and higher rates are observed with anti-TNF Abs (e.g., infliximab) as compared with TNF receptor fusion protein (etanercept). Mechanisms driving differential reactivation rates and differences in drug action are not known. We use a computational model of a TB granuloma formation that includes TNF/TNF receptor dynamics to elucidate these mechanisms. Our analyses yield three important insights. First, drug binding to membrane-bound TNF critically impairs granuloma function. Second, a higher risk of reactivation induced from Ab-type treatments is primarily due to differences in TNF/drug binding kinetics and permeability. Apoptotic and cytolytic activities of Abs and pharmacokinetic fluctuations in blood concentration of drug are not essential to inducing TB reactivation. Third, we predict specific host factors that, if augmented, would improve granuloma function during anti-TNF therapy. Our findings have implications for the development of safer anti-TNF drugs to treat inflammatory diseases.
在接受 TNF-α（TNF）中和药物治疗的人群中，结核病（TB）再激活的发生率增加，并且与 TNF 受体融合蛋白（依那西普）相比，使用抗 TNF Abs（例如英夫利昔单抗）观察到更高的再激活率。驱动差异再激活率和药物作用差异的机制尚不清楚。我们使用包括 TNF/TNF 受体动力学的 TB 肉芽肿形成的计算模型来阐明这些机制。我们的分析产生了三个重要的见解。首先，药物与膜结合型 TNF 的结合严重损害了肉芽肿的功能。其次，Ab 型治疗引起的再激活风险较高，主要是由于 TNF/药物结合动力学和通透性的差异。Abs 的凋亡和细胞溶解活性以及药物在血液中的浓度的药代动力学波动对于诱导 TB 再激活并非必不可少。第三，我们预测了特定的宿主因素，如果增强，将在抗 TNF 治疗期间改善肉芽肿功能。我们的发现对开发更安全的抗 TNF 药物治疗炎症性疾病具有重要意义。
