2010 Fiscal Year Final Research Report
Colitogenic memory T cells are maintained by IL-7-producing cells in bone marrow.
| Project/Area Number |
20590736
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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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 | Tokyo Medical and Dental University |
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Principal Investigator |
NEMOTO Yasuhiro Tokyo Medical and Dental University, 大学院・医歯学総合研究科, GCOE拠点形成特任教員 (20456213)
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| Co-Investigator(Kenkyū-buntansha) |
渡辺 守 東京医科歯科大学, 大学院・医歯学総合研究科・消化器病態学, 教授 (10175127)
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| Project Period (FY) |
2008 – 2010
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| Keywords | 炎症性腸疾患 / IL-7 / メモリーT細胞 / 骨髄 / 腸内細菌 / 無菌マウス / 間葉系幹細胞 / CD4^+ T細胞 |
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| Research Abstract |
The aim of this study is to clarify the maintenance system of colitogenic memory CD4^+ T cells, which posses the "pathogenic memory" of inflammatory bowel disease, and to develop the epoch-making treatment for this disease.
We have proved following things. 1) Although intestinal bacteria is essential for the development of colitis and cytokine production from effector T cells, it is not essential for the maintenance of colitogenic memory CD4^+ T cells. 2) IL-7^<-/-> x RAG-1^<-/-> mice were transplanted with BM cells of RAG-1^<-/-> (IL-7^<+/+>→IL-7^<-/->) or IL-7^<-/-> x RAG-1^<-/-> mice (IL-7^<-/->→IL-7^<-/->). IL-7 mRNA and protein were detected in BM, but not in colon, of in IL-7^<+/+>→IL-7^<-/-> mice, but not from IL-7^<-/->→IL-7^<-/-> mice. IL-7^<+/+>→IL-7^<-/->, but not IL-7^<-/->→IL-7^<-/-> recipients, transferred with CD4^+CD45RB^<high> T cells 4 weeks after transplantation, developed colitis. 3) Bone marrow mesenchymal stem cells (MSC), even over the 40^<th> passage, expressed ^<high>er levels of IL-7 mRNA and protein than those of freshly isolated IL-7^+ BM cells. 4) Co-culture with IL-7 producing MSC induced extensive proliferation of CFSE-labeled colitogenic CD4^+ T cells in vitro. 5) CD4^+CD45RB^<high> T cell-transferred IL-7^<-/-> x RAG-1^<-/-> mice previously transplanted with IL-7 producing MSC developed Th1/Th17-meidated colitis.
Collectively, IL-7 producing bone marrow MSC play the important role in the maintenance system of colitogenic memory CD4^+ T cells. These findings are the progress in the investigation of IBD pathogenesis, suggesting the possibility of novel effective treatment, which targets this system.
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