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

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基于我们的原始概念，将局部免疫反应操纵和人类肠内组织再生诱导的诱导。在相应的两年研究中，我们在初步研究计划后完成了一系列研究，并取得了以下结果。 1）我们已经表明，来自肠上皮细胞的IL-7产生与结肠炎的诱导密切相关，并且表达高水平IL-7受体的淋巴细胞可能是治疗CHRO…更多NIC结肠炎的新靶标（AM J Physiol，Am J Physiol，2005年，印刷中）。 2）我们已经证明了肠上皮细胞产生IL-7的新机制，具体取决于转录因子IRF-1和IRF-2，并提供了证据，表明操纵IRF依赖性转录可能有效地治疗慢性结肠炎（Mol Cell Biol Biol 2004）。 3）我们还证明了IRE-1在肠道的杯状细胞中特别表达，并用作免疫蛋白酶体亚基的一致表达的主开关，这提供了进一步的证据，表明杯状细胞在肠内免疫激发调节中起特定的作用（Febs Lett，2005年，印刷中）。 4）最后，我们证明，骨髓衍生的细胞通过提供增加骨髓衍生的分泌型上皮细胞（包括与3个小腿）的骨髓上皮细胞的再生，这些细胞（包括杯状细胞）为谱系特异性，特定于特定的，转移性居住疗法提供了科学基础，并为2005年的200555固定。因此，本研究中进行的前四个主要项目提供了各种有意义的结果，这将导致建立新型策略，以表达慢性结肠炎或食物过敏和再生疗法的肠道疗法，通过整合肠粘膜免疫反应和诱导组织再生的调节。较少的

项目成果

Ezaki T, Watanabe M, et al.: "A specific genetic alteration on chromosome 6 in ulcerative colitis-associated colorectal cancers."Cancer Res. 63. 3747-3749 (2003)

Ezaki T、Watanabe M 等人：“溃疡性结肠炎相关结直肠癌中 6 号染色体上的特定遗传改变。”Cancer Res。

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.

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。

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”。

Uraushihara K, Watanabe M, et al.: "Regulation of murine inflammatory bowel disease by CD25+ and CD25-CD4+ glucocorticoid-induced TNF receptor family-related gene+ regulatory T cells."J Immunol. 171. 708-716 (2003)

Uraushihara K、Watanabe M 等人：“CD25 和 CD25-CD4 糖皮质激素诱导的 TNF 受体家族相关基因调节 T 细胞对小鼠炎症性肠病的调节”。