Yamazaki Motomi, Yajima Tomoharu, Tanabe Masanobu, Fukui Kazuto, Okada Eriko, Okamoto Ryuichi, Oshima Shigeru, Nakamura Tetsuya, Kanai Takanori, Uehira Masahiro, Takeuchi Tsutomu, Ishikawa Hiromichi, Hibi Toshifumi, Watanabe Mamoru
Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
J Immunol. 2003 Aug 1;171(3):1556-63. doi: 10.4049/jimmunol.171.3.1556.
The IL-7/IL-7R-dependent signaling pathway plays a crucial role in regulating the immune response in intestinal mucosa. Here we demonstrate the pivotal role of this pathway in the development and treatment of chronic colitis. T cells expressing high levels of IL-7R were substantially infiltrated in the chronic inflamed mucosa of TCR alpha-chain knockout mice and IL-7 transgenic mice. Transfer of mucosal T cells expressing high levels of IL-7R, but not T cells expressing low levels of IL-7R, from these mice into recombinase-activating gene-2(-/-) mice induced chronic colitis. Selective elimination of T cells expressing high levels of IL-7R by administrating small amounts of toxin-conjugated anti-IL-7R Ab completely ameliorated established, ongoing colitis. These findings provide evidence that therapeutic approaches targeting mucosal T cells expressing high levels of IL-7R are effective in the treatment of chronic intestinal inflammation and may be feasible for use in the therapy of human inflammatory bowel disease.
白细胞介素-7/白细胞介素-7受体依赖性信号通路在调节肠道黏膜免疫反应中起关键作用。在此，我们证明了该通路在慢性结肠炎的发生发展及治疗中的关键作用。在TCRα链敲除小鼠和白细胞介素-7转基因小鼠的慢性炎症黏膜中，大量浸润了高表达白细胞介素-7受体的T细胞。将这些小鼠中高表达白细胞介素-7受体的黏膜T细胞而非低表达白细胞介素-7受体的T细胞转移至重组激活基因-2(-/-)小鼠中，可诱发慢性结肠炎。通过给予少量毒素偶联的抗白细胞介素-7受体抗体选择性清除高表达白细胞介素-7受体的T细胞，可完全改善已形成的、正在进行的结肠炎。这些发现提供了证据，表明针对高表达白细胞介素-7受体的黏膜T细胞的治疗方法在治疗慢性肠道炎症方面是有效的，并且可能适用于人类炎症性肠病的治疗。
