2003 Fiscal Year Final Research Report Summary
Basic research on ex vivo modification of dendritic cell functions for development of treatment for inflammatory bowel diseases
| Project/Area Number |
13470124
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Gastroenterology
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| Research Institution | Research Institute, International Medical Center of Japan |
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Principal Investigator |
DOHI Taeko Research Institute, International Medical Center of Japan, Dept of Gastroenterology, 消化器疾患研究部, 部長 (60250221)
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| Co-Investigator(Kenkyū-buntansha) |
KIRIKAE Teruo Research Institute, International Medical Center of Japan, Dept of Tropical diseases nad Infection, 熱帯感染症研究部, 部長 (50192563)
MATSUSHIMA Kouji University of Tokyo, Graduate School of Medicine, Department of Molecular Preventive Medicine and Solution Oriented Research for Science and Technology, 大学院・医学系研究科・分子予防医学, 教授 (50222427)
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| Project Period (FY) |
2001 – 2003
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| Keywords | Ulcerative colitis / Dendritic cells / Peyer's patches / Cytokines / Chemokines / Commensal flora / lipopolysaccharides / inflammatory bowel disease |
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| Research Abstract |
The purpose of this project was to clarify the function of dendritic cells (DC) in normal murine gastrointestinal (GI) tract as well as human GI tract in terms of the characteristic hyporesponsiveness to normal commensal flora, to develop a new remedy for inflammatory bowel disease.
1.In a mouse model for ulcerative colitis (UC), recruitment of dendritic cells contributed to the perpetuation of disease, which was efficiently blocked by a soluble form chimeric protein of lymphotoxin β receptor.
2.Human colonic macrophages and dendritic cells showed low cytokine responses after. stimulation with lipopolysaccharides (LPS), which was due to lack of MD-2, an essential molecule for LPS-signaling via toll like receptor 4. Further analysis of colonic cell obtained from UC patients showed aberrant expression of MD-2 and cytokines.
3.We found that adoptively transferred DCs were localized in mesenteric lymph nodes. It indicated the possibility of modulation of mucosal immunity by exogenous DC.
4.Because the significant side effect of retroviral vector was revealed during the research period, we searched other methods to modify function of DC ex vivo. We analyzed the effect of cholera toxin (CT) and CT was able to fully activate DC by activation NF-κB which was dependent on the binding to cell surface GM1 ganglioside.
5.To develop a methods to deliver molecules into DC utilizing intracelluer transport, we created new double mCTs (dmCTs) that have two amino acid substitutions in the ADP-ribosyltransferase active center (E112K) and COOH-terminal KDEL (E112K/KDEV or E112K/KDGL). KDEL mutant was transported to Golgi but not to ER.
Results of these serial experiment listed above provided important and basic knowledge to develop new remedies for the treatment of inflammatory bowel disease by modifying the function of dendritic cells ex vivo.
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