Evaluation of the Therapeutic Potential of Anti-TLR4-Antibody MTS510 in Experimental Stroke and Significance of Different Routes of Application.
Evaluation of the Therapeutic Potential of Anti-TLR4-Antibody MTS510 in Experimental Stroke and Significance of Different Routes of Application.
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DOI：
10.1371/journal.pone.0148428
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Trendelenburg G
中科院分区：
文献类型：
--
作者：
Andresen L;Theodorou K;Grünewald S;Czech-Zechmeister B;Könnecke B;Lühder F;Trendelenburg G
Toll样受体是脑缺血再灌注损伤中炎症反应的中枢感受器。因此，我们在局灶性脑缺血的标准模型中研究了TLR4抑制是否可以用于治疗中风。先前报道，抗TLR4/MD2抗体(mAb克隆MTS510)在体外可阻断TLR4诱导的细胞激活。在成年雄性C57BL/6野生型小鼠大脑中动脉(MCAO)闭塞45min后，采用不同途径体内应用MTS510，研究MTS510对卒中结局的影响。MTS510对45min MCAO模型的神经功能改善、脑梗塞体积缩小、脑肿胀减轻均有保护作用。对抗TLR4单抗治疗的潜在长期不良反应的评估显示，在轻度卒中模型(15min MCAO)再灌注14d后，TLR4单抗治疗对脑梗塞体积和神经功能障碍没有显著的有害影响。有趣的是，抑制TLR4导致再灌流后48小时的获得性免疫反应改变。我们得出结论，用特异性单抗阻断TLR4是一种很有前途的卒中治疗策略。然而，在设想临床应用之前，需要进行功能敏感度提高、样本量更大和使用其他物种的长期研究。
Toll-like receptors (TLRs) are central sensors for the inflammatory response in ischemia-reperfusion injury. We therefore investigated whether TLR4 inhibition could be used to treat stroke in a standard model of focal cerebral ischemia. Anti-TLR4/MD2-antibody (mAb clone MTS510) blocked TLR4-induced cell activation in vitro, as reported previously. Here, different routes of MTS510 application in vivo were used to study the effects on stroke outcome up to 2d after occlusion of the middle cerebral artery (MCAO) for 45min in adult male C57Bl/6 wild-type mice. Improved neurological performance, reduced infarct volumes, and reduced brain swelling showed that intravascular application of MTS510 had a protective effect in the model of 45min MCAO. Evaluation of potential long-term adverse effects of anti-TLR4-mAb-treament revealed no significant deleterious effect on infarct volumes nor neurological deficit after 14d of reperfusion in a mild model of stroke (15min MCAO). Interestingly, inhibition of TLR4 resulted in an altered adaptive immune response at 48 hours after reperfusion. We conclude that blocking TLR4 by the use of specific mAb is a promising strategy for stroke therapy. However, long-term studies with increased functional sensitivity, larger sampling sizes and use of other species are required before a clinical use could be envisaged.