Development of a novel therapy for the treatment of chronic colitis based on the manipulation of mucosal immune response and the clarification of tissue specific system for epithelial regeneration.

基于粘膜免疫反应的操纵和上皮再生组织特异性系统的阐明，开发一种治疗慢性结肠炎的新疗法。

• 批准号: 15390229
• 负责人: WATANABE Mamoru
• 金额: $ 9.22万
• 依托单位: Tokyo Medical and Dental University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15390229/
• 关键词: mucosal immunity; IL-7; intestinal epithelial cell; cell differentiation; chronic colitis; transcriptional factor; bone marrow cell; regenerative medicine; 消化管粘膜免疫; 粘膜IL-7; IL-7レセプター機構; 腸管上皮細胞分化; サイトカイン; Interferon Regulatory Factor (IRF); 骨

The present study was a sprouting study following our original findings of the IL-7/IL-7 receptor system within the intesine, and provided successful findings in the area of human mucosal immunology, such as the origin of intestinal epithelial cells, the mechanism of the growth and differentiation of intestinal lymphocytes or interactions between mucosal epithelial cells and lymphocytes, all of which were aimed to establish a novel therapy for chronic colitis based on our original concept integrating the manipulation of the local immune response and induction of tissue regeneration within the human intestine. During the corresponding two years of study, we have accomplished series of studies following our initial study plan, and have achieved following results. 1)We have showed that IL-7 production from intestinal epithelial cells is closely involved in the induction of colitis, and that lymphocytes expressing high levels of IL-7 receptor may be a novel target for the treatment of chro … More nic colitis (Am J Physiol, 2005, in press). 2)We have demonstrated the novel mechanism of IL-7 production by intestinal epithelial cells depending on transcription factors IRF-1 and IRF-2, and provided evidences that manipulation of IRF-dependent transcription may be effective for the treatment of chronic colitis (Mol Cell Biol 2004). 3)We also demonstrated that IRE-1 is expressed specifically in goblet cells of the intestine, and functions as a master switch for the concerted expression of immuno-proteasome subunits, which provides further evidences that goblet cells play specific roles in the regulation of immune response within the intestine (FEBS Lett, 2005, in press). 4)Finally, we demonstrated that bone marrow derived cells rescue the regeneration of intestinal epithelial cells by providing increased number of bone marrow-derived secretory-type epithelial cells (including goblet cells), which in combination with 3), provided scientific basis for the establishment of lineage-specific, inductive regeneration therapy (Gastroenterology, 2005, in press). Consequently, the previous four major projects conducted in the present study have provided various meaningful results which would lead to the establishment of both novel strategy for the repression of chronic colitis or food allergy and regenerative therapy of the intestine, by integrating the regulation of intestinal mucosal immune response and the induction of tissue regeneration. Less

本研究是继我们最初发现肠内IL-7/IL-7受体系统之后的一项萌芽研究，在人类粘膜免疫学领域提供了成功的发现，如肠上皮细胞的起源、肠淋巴细胞的生长和分化机制或粘膜上皮细胞与淋巴细胞之间的相互作用，所有这些都旨在建立一种新的治疗方法 基于我们最初的概念，将局部免疫反应的操纵和人体肠道内组织再生的诱导结合起来，用于治疗慢性结肠炎。在相应的两年学习期间，我们按照最初的学习计划完成了一系列的研究，并取得了以下成果。 1)我们已经表明，肠上皮细胞产生的IL-7与结肠炎的诱发密切相关，并且表达高水平IL-7受体的淋巴细胞可能是治疗慢性结肠炎的新靶标（Am J Physiol，2005，印刷中）。 2）我们已经证明了肠上皮细胞依赖于转录因子IRF-1和IRF-2产生IL-7的新机制，并提供了证据表明操纵IRF依赖性转录可能对慢性结肠炎的治疗有效（Mol Cell Biol 2004）。 3)我们还证明IRE-1在肠道杯状细胞中特异性表达，并作为免疫蛋白酶体亚基协同表达的主开关，这进一步证明杯状细胞在肠道内免疫反应的调节中发挥特定作用(FEBS Lett, 2005, in press)。 4）最后，我们证明骨髓来源的细胞通过提供增加数量的骨髓来源的分泌型上皮细胞（包括杯状细胞）来拯救肠上皮细胞的再生，这与3）结合，为谱系特异性诱导再生疗法的建立提供了科学依据（Gastroenterology，2005，出版中）。因此，本研究之前进行的四个主要项目提供了各种有意义的结果，这些结果将导致通过整合肠粘膜免疫反应的调节和组织再生的诱导来建立抑制慢性结肠炎或食物过敏和肠道再生治疗的新策略。较少的

项目成果

Interferon regulatory factor 1 (IRF-1) and IRF-2 distinctively up-regulate gene expression and production of interleukin-7 in human intestinal epithelial cells

• DOI: 10.1128/mcb.24.14.6298-6310.2004
• 发表时间: 2004-07-01
• 期刊: MOLECULAR AND CELLULAR BIOLOGY
• 影响因子: 5.3
• 作者: Oshima, S;Nakamura, T;Watanabe, M
• 通讯作者: Watanabe, M

Yanazaki M, Watanabe M, et al.: "Mucosal T cells expressing high levels of IL-7 receptor are potential targets for treatment of chronic colitis."J Immunol. 171. 1556-1563 (2003)

Yanazaki M、Watanabe M 等人：“表达高水平 IL-7 受体的粘膜 T 细胞是治疗慢性结肠炎的潜在靶标”。

Totsuka T, Watanabe M, et al.: "Ameliorating effect of anti-inducible co-stimulator monoclonal antibody in a murine model of chronic colitis."Gastroenterology. 124. 410-421 (2003)

Totsuka T、Watanabe M 等人：“抗诱导共刺激单克隆抗体在慢性结肠炎小鼠模型中的改善作用。”胃肠病学。

Increase of bone marrow-derived secretory lineage epithelial cells during regeneration in the human intestine

• DOI: 10.1053/j.gastro.2005.03.085
• 发表时间: 2005-06-01
• 期刊: GASTROENTEROLOGY
• 影响因子: 29.4
• 作者: Matsumoto, T;Okamoto, R;Watanabe, M
• 通讯作者: Watanabe, M

Increase of bone marrow-derived secretary lineage epithelial cells during regeneration in the human intestine.

人肠道再生过程中骨髓来源的秘书谱系上皮细胞的增加。

• 发表时间: 2005
• 期刊: Gastroenterology. (in press)
• 作者: Matsumoto T;Okamoto R;Yajima T;Mori T;Okamoto S;Ikeda Y;Mukai M;Yamazaki M;Nakamura T;Kanai T;Hibi T;Inazawa J;Watanabe M.
• 通讯作者: Watanabe M.