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Permanent cure strategy of inflammatory bowel diseases by inducing immunological reset

通过诱导免疫重置永久治愈炎症性肠病的策略

基本信息

批准号：
21390233
负责人：
KANAI Takanori
金额：
$ 11.65万
依托单位：
Keio University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2009
资助国家：
日本
起止时间：
2009 至 2011
项目状态：
已结题

项目摘要

Despite the advent of an age when "malignant" leukemia is cured by bone marrow transplantation, "benign" inflammatory bowel diseases(IBD) are still intractable lifelong diseases. We showed that immune memory T cells that remember the disease are formed in IBD, and perceiving them as "benign T-cell leukemia"-like lifelong pathology that spreads throughout the body, We demonstrated that interleukin-7(IL-7) and commensal bacteria are essential as a survival factor for the maintenance and proliferation of colitogenic CD4^+memory T cells, in IBD. Although IL-17A is thought to be preferentially produced by T_h17 cells and to play a critical role in autoimmune disease development, it seems to inhibit development of T_h1 cells in some circumstances. Colitogenic T_h1 cells and T_h17 cells seem to interfere with each other in vivo under inflammatory conditions. At least in inflammatory conditions, colitogenic T_h1 cells and T_h17 cells are not independently generated ; rather the linear sequential developmental pathway from T_h17 to Th1 cells seems to dominate. Further study is needed to determine whether the classical T_h1 cells directly generated from naive T cells in an RORγt-independent manner are also involved in IBD pathogenesis. The pathway from T_h17/T_h1 cells to alternative T_h1 cells is suppressed by T_<reg> cells, resulting in the accumulation of T_h17 cells by T_<reg> cells.

尽管“恶性”白血病可以通过骨髓移植治愈的时代已经到来，但“良性”炎症性肠病（IBD）仍然是终身难治的疾病。我们证明，在 IBD 中形成了记忆疾病的免疫记忆 T 细胞，并将其视为“良性 T 细胞白血病”样的终身病理学，并扩散到全身。我们证明，白细胞介素 7 (IL-7) 和共生细菌作为 IBD 中致结肠炎 CD4^+ 记忆 T 细胞维持和增殖的生存因子至关重要。尽管IL-17A被认为优先由T_h17细胞产生并在自身免疫性疾病的发展中发挥关键作用，但在某些情况下它似乎会抑制T_h1细胞的发育。在炎症条件下，致结肠炎 T_h1 细胞和 T_h17 细胞似乎在体内相互干扰。至少在炎症条件下，致结肠炎T_h1细胞和T_h17细胞不是独立产生的；相反，从 T_h17 到 Th1 细胞的线性顺序发育途径似乎占主导地位。需要进一步研究以确定以不依赖 RORγt 的方式直接从初始 T 细胞产生的经典 T_h1 细胞是否也参与 IBD 发病机制。从T_h17/T_h1细胞到替代T_h1细胞的途径被T_<reg>细胞抑制，导致T_<reg>细胞积累T_h17细胞。

项目成果

期刊论文数量（0）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Long-lived Colitogenic C04+Memory T Cells can be Maintained Outside the Intestine in the Absence of Commesal Bacteria

在没有共生细菌的情况下，长寿命致结肠炎 C04 记忆 T 细胞可以在肠外维持

DOI：
发表时间：
2009
期刊：
影响因子：
0
作者：
根本泰宏;金井隆典;松本敏;渡辺守
通讯作者：
渡辺守

Signaling pathway via TNF-α/NF-κB in intestinal epithelial cells may be directly involved in colitis-associated carcinogenesis

DOI：
10.1152/ajpgi.00071.2008
发表时间：
2009-04-01
期刊：
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
影响因子：
4.5
作者：
Onizawa, Michio;Nagaishi, Takashi;Watanabe, Mamoru
通讯作者：
Watanabe, Mamoru

RANK-RANKL signaling pathway is critically involved in the function 0f CD4+CD25+regulatory T cells in chronic colitis

RANK-RANKL信号通路关键参与慢性结肠炎0f CD4 CD25调节性T细胞的功能

DOI：
发表时间：
2009
期刊：
J Immunol
影响因子：
4.4
作者：
Totsuka T;Kanai T;et al.
通讯作者：
et al.

Upregulated IL-7 Receptor {alpha} Expression on Colitogenic Memory CD4+ T Cells May Participate in the Development and Persistence of Chronic Colitis.

致结肠炎记忆 CD4 T 细胞上 IL-7 受体 {α} 表达的上调可能参与慢性结肠炎的发展和持续。

DOI：
发表时间：
2011
期刊：
J Immunol. in press
影响因子：
0
作者：
Shinohara T;Nemoto Y;Kanai T;Kameyama K;Okamoto R;Tsuchiya K;Nakamura T;Totsuka T;Ikuta K;Watanabe M
通讯作者：
Watanabe M

CCR9+ Macrophages Are Required for Acute Liver Inflammation in Mouse Models of Hepatitis