2005 Fiscal Year Final Research Report Summary
A novel mucosal immunomodulator MICA for homeostasis of the mucosal immune system
| Project/Area Number |
16590406
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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 |
Immunology
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| Research Institution | HIROSHIMA UNIVERSITY |
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Principal Investigator |
TAKAHASHI Ichiro Hiroshima University, Graduate School of Biomedical Sciences, Professor, 大学院・医歯薬学総合研究科, 教授 (20206791)
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| Project Period (FY) |
2004 – 2005
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| Keywords | mucosal immunity / MICA / intraepithelial lymphocytes / inflammatory bowel disease / IL-15 / NKG2D |
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| Research Abstract |
Immunological significances of NKG2D ligands have been intensively investigated. While human NKG2D binds to MICA and MICB, ligands for murine NKG2D are quite different such as H60 and members of the Rae 1 family. All NKG2D ligands identified so far share the characteristic that expression on the cell surface is almost undetectable in normal tissues, but can be induced by a variety of different types of cell stress. Recent paper reported that villous atrophy in active celiac disease could be caused by an IEL-mediated damage to enterocytes involving NKG2D/MICA interaction after IL-15-relayed expression of MICA on gut epithelium. Based on these findings, NKG2D^+, innate T cells persisted in the mucosa could be involved in mucosal inflammation by NKG2D/MICA interaction. In this study, we examined how mucosal epithelial cells derived-IL-15 and MICA affect the induction and development of mucosal inflammation in TCR α^<-/-> mice.
Dysregulation of mucosal intranet between aberrant Th2-type, ββ
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T cells and colonic epithelial cells is involved in the pathogenesis of inflammatory bowel disease in TCRα-chain deficient mice. We initially noticed an increase of IL-15 mRNA expression in the colonic epithelial cells of the diseased mice, and ββT cells isolated from the diseased colon possessed all the subunits of IL-15 receptor and the ability to proliferate in response to IL-15. Furthermore, histopathological examination of TL promoter-driven IL-15 transgenic TCR-chain deficient mice showed that the double mutant mice displayed an increase in the severity of colitis in comparison to TCR-chain deficient mice. The number of ββT cells infiltrated in the diseased colon was increased. Enhanced expression of Bcl-2 as well as NKG2D was also noted in the colonic ββT cells from the double mutant mice. These data suggested that aberrant IL-15 signaling was involved in the development and survival of aberrant ββT cells that had the ability to exacerbate the colitis. To investigate the in vivo effect of MICA for the development of colitis, ββT cells from the diseased colon in TCR^<-/-> mice were transferred into MICA transgenic RAG^<-/-> mice. The results showed that MICA transgenic RAG^<-/-> recipients delayed the onset of colitis in comparison to RAG^<-/-> mice. Thus, we speculate that although aberrant IL-15 expression was involved in the colitis exacerbation, constitutive MICA expression could participate in the suppression of colitis development. Less
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Research Products
(9 results)
