Development of novel therapy targeting innate immunity for Crohn's disease

针对克罗恩病先天免疫的新疗法的开发

• 批准号: 17590678
• 负责人: IWAO Yasushi
• 金额: $ 2.3万
• 依托单位: KEIO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590678/
• 关键词: Crohn's disease; dendritic cell; macrophage; innate immunity; inflammatory bowel disease; Th1; Th2

Crohn's disease (CD) is a chronic inflammatory process involving the gastrointestinal tract, characterized by discontinuous and transmural inflammation. Although the etiology of CD is not fully understood, accumulating evidence suggests that dysregulation of the local immune system is pivotal in the pathogenesis of CD. Studies from humans and experimental murine colitis models indicate that in CD, the local immune response tends to be predominantly T helper cell type 1 (Th1) and is reflected by local release of cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-12, and IL-18. However, it has not been elucidated what triggers the Th1 immune response in CD. In the present study, we attempted to establish the purification of dendritic cells from mesenteric lymph nodes (MLN) and to analyze the immune cascade in the mesenteric lymph nodes of human CD.We established the purification of dendritic cells from MLN by density gradient centrifugation and immunomagnetic depletion of CD3^+,CD11b^+ and CD16^+cells followed by positive isolation with CD4^+. The analysis of cells obtained from MLNs revealed that the proportion of DC1 was increased in the MLN of CD compared to ulcerative colitis and control and that CD4+ T lymphocytes from the MLN of CD show a Th1 profile.Furthermore, we tried to elucidate the roles of macrophages in intestinal inflammation by using an IL-10-deficient (IL-10-/-) mouse colitis model, and demonstrated that abnormally differentiated subsets of intestinal macrophage play a key role in Th1-dominant chronic colitis through excess production of IL-12 and IL-23 in response to bacteria. These data provide new insights into the intestinal macrophages to gut flora relationship in the development of colitis in IL-10-/- mice.

克罗恩病（CD）是一种累及胃肠道的慢性炎症过程，其特征在于不连续和透壁炎症。虽然CD的病因尚未完全清楚，但越来越多的证据表明，局部免疫系统的失调在CD的发病机制中至关重要。对人类和实验性小鼠结肠炎模型的研究表明，在CD中，局部免疫应答往往主要是1型T辅助细胞（Th 1），并通过局部释放细胞因子（如肿瘤坏死因子（TNF）-α、白细胞介素（IL）-12和IL-18）反映。然而，还没有阐明是什么触发CD中的Th 1免疫应答。本研究采用密度梯度离心、免疫磁珠法去除CD 3 ^+、CD 11b ^+和CD 16 ^+细胞，再用CD 4 ^+细胞进行阳性分离，建立了从人CD肠系膜淋巴结（MLN）中分离纯化树突状细胞的方法，并对MLN中的免疫级联反应进行了分析。从MLN中获得的细胞分析显示，与溃疡性结肠炎和对照组相比，CD MLN中DC 1的比例增加，CD MLN中的CD 4 + T淋巴细胞显示Th 1特征。（IL-10-/-）小鼠结肠炎模型，并证明肠巨噬细胞的异常分化的亚群通过响应细菌过量产生IL-12和IL-23在Th 1-显性慢性结肠炎中起关键作用。这些数据为IL-10-/-小鼠结肠炎发展过程中肠巨噬细胞与肠道植物群的关系提供了新的见解。

项目成果

A novel apoptosis-inducing monoclonal antibody (anti-LHK) against a cell surface antigen on colon cancer cells.

一种针对结肠癌细胞上细胞表面抗原的新型凋亡诱导单克隆抗体（抗 LHK）。

• 发表时间: 2005
• 期刊: J Gastroenterol 40・10
• 作者: Matsukawa H;Watanabe M et al.
• 通讯作者: Watanabe M et al.

A new technique for endoscopic submucosal dissection for early gastric cancer using an external grasping forceps

• DOI: 10.1055/s-2006-925264
• 发表时间: 2006-10-01
• 期刊: ENDOSCOPY
• 影响因子: 9.3
• 作者: Imaeda, H.;Iwao, Y.;Hibi, T.
• 通讯作者: Hibi, T.

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

Association of pseudomembranous colitis with Henoch-Schonlein purpura.

伪膜性结肠炎与过敏性紫癜的关联。

• 发表时间: 2005
• 期刊: J Gastroenterol 40・6
• 作者: Hayakawa T;Iwao Y et al.
• 通讯作者: Iwao Y et al.

Clinical significance of serum p53 antibodies in patients with ulcerative colitis and its carcinogenesis

• DOI: 10.1002/ibd.20112
• 发表时间: 2007-07
• 期刊: Inflammatory Bowel Diseases
• 影响因子: 4.9
• 作者: S. Yoshizawa;K. Matsuoka;N. Inoue;H. Takaishi;H. Ogata;Y. Iwao;M. Mukai;T. Fujita;Y. Kawakami;T. Hibi