The therapeutic effect of TNFR1-selective antagonistic mutant TNF-α in murine hepatitis models
The therapeutic effect of TNFR1-selective antagonistic mutant TNF-α in murine hepatitis models
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DOI：
10.1016/j.cyto.2008.07.003
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发表时间：
2008-11-01
期刊：
影响因子：
3.8
通讯作者：
Tsutsumi, Yasuo
中科院分区：
文献类型：
--
作者：
Shibata, Hiroko;Yoshioka, Yasuo;Tsutsumi, Yasuo
肿瘤坏死因子-α（TNF-α）通过TNF受体-1（TNFR 1）与多种炎症性病理如肝炎密切相关。为了开发TNFR 1靶向抗炎药物，我们已经成功地创建了TNFR 1选择性拮抗突变体TNF-α（R1 antTNF），并显示R1 antTNF在体外有效抑制TNF-α/TNFR 1介导的生物活性。在这项研究中，我们使用两个独立的实验模型，四氯化碳（CCl 4）或刀豆球蛋白A（ConA）诱导的急性肝炎，研究R1 antTNF的治疗效果。在CCl 4诱导的模型中，用R1 antTNF治疗显著抑制了ALT（丙氨酸转氨酶）血清水平的升高，ALT是肝损伤的标志物。在ConA诱导的T细胞介导的肝炎模型中，R1 antTNF还抑制血清免疫活化标志物如IL-2和IL-6的产生。这些R1 antTNF介导的治疗效果与使用常规抗TNF-α抗体治疗获得的效果一样好或更好。我们的研究结果表明，R1 antTNF可能是一种临床上有用的TNF-α拮抗剂在肝炎。(C)2008爱思唯尔有限公司保留所有权利。
Tumor necrosis factor-alpha (TNF-alpha) is critically involved in a wide variety of inflammatory pathologies, such as hepatitis, via the TNF receptor-1 (TNFR1). To develop TNFR1-targeted anti-inflammatory drugs, we have already succeeded in creating a TNFR1-selective antagonistic mutant TNF-alpha (R1antTNF) and shown that R1antTNF efficiently inhibits TNF-alpha/TNFR1-mediated biological activity in vitro. In this study, we examined the therapeutic effect of R1antTNF in acute hepatitis using two independent experimental models, induced by carbon tetrachloride (CCl4) or concanavalin A (ConA). In a CCl4-induced model, treatment with R1antTNF significantly inhibited elevation in the serum level of ALT (alanine aminotransferase), a marker for liver damage. In a ConA-induced T-cell-mediated hepatitis model, R1antTNF also inhibited the production of serum immune activated markers such as IL-2 and IL-6. These R1antTNF-mediated therapeutic effects were as good as or better than those obtained using conventional anti-TNF-alpha antibody therapy. Our results suggest that R1antTNF may be a clinically useful TNF-alpha antagonist in hepatitis. (C) 2008 Elsevier Ltd. All rights reserved.