Laboratory of Pharmaceutical Proteomics, National Institute of Biomedical Innovation (NiBio), 7-6-8 Saito-Asagi, Ibaraki, Osaka 567-0085, Japan.
J Control Release. 2011 Jan 5;149(1):8-14. doi: 10.1016/j.jconrel.2009.12.015. Epub 2009 Dec 24.
Multiple sclerosis (MS) is an inflammatory demyelinating disease, the pathogenesis of which is related to elevated serum levels of tumor necrosis factor-α (TNF). Although anti-TNF therapy has been tested as a potential treatment for MS, no remission of symptoms was observed. Recent reports indicated that the TNFR1 signal was responsible for the pathogenesis of murine experimental autoimmune encephalomyelitis (EAE), while the TNFR2 signal was responsible for recovery of the pathogenesis of EAE. Therefore, selective blocking of TNFR1 appears to be a promising strategy for the treatment of MS. In this regard, we previously succeeded in developing a novel TNFR1-selective antagonistic TNF mutant (R1antTNF) by using phage display technology. Here, we have examined the therapeutic potential of R1antTNF using EAE mice. Treatment with PEGylated R1antTNF (PEG-R1antTNF) significantly improved the clinical score and cerebral demyelination at the onset of EAE. Considerable suppression of Th1 and Th17-type response was also observed in spleen and lymph node cells of mice given PEG-R1antTNF. Moreover, the administration of PEG-R1antTNF suppressed the infiltration of inflammatory cells containing Th1 and Th17 cells into the spinal cord. These results suggest that selective blocking of TNFR1 by PEG-R1antTNF could be an effective therapeutic strategy against MS.
多发性硬化症（MS）是一种炎症性脱髓鞘疾病，其发病机制与肿瘤坏死因子-α（TNF）血清水平升高有关。尽管抗 TNF 治疗已被尝试作为 MS 的潜在治疗方法，但并未观察到症状缓解。最近的报告表明，TNFR1 信号负责实验性自身免疫性脑脊髓炎（EAE）的发病机制，而 TNFR2 信号负责 EAE 发病机制的恢复。因此，选择性阻断 TNFR1 似乎是治疗 MS 的一种有前途的策略。在这方面，我们之前成功地使用噬菌体展示技术开发了一种新型 TNFR1 选择性拮抗 TNF 突变体（R1antTNF）。在这里，我们使用 EAE 小鼠检查了 R1antTNF 的治疗潜力。用聚乙二醇化 R1antTNF（PEG-R1antTNF）治疗可显著改善 EAE 发病时的临床评分和大脑脱髓鞘。给予 PEG-R1antTNF 的小鼠脾脏和淋巴结细胞中也观察到 Th1 和 Th17 型反应的明显抑制。此外，PEG-R1antTNF 的给药抑制了含有 Th1 和 Th17 细胞的炎症细胞浸润脊髓。这些结果表明，PEG-R1antTNF 对 TNFR1 的选择性阻断可能是治疗 MS 的有效治疗策略。
