Molecular and cellular mechanisms of the chronic GVHD-associated impairment of bone marrow hematopoietic niche
| Project/Area Number |
16K08730
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Experimental pathology
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| Research Institution | Tokyo University of Science (2018)
The University of Tokyo (2016-2017) |
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Principal Investigator |
Ueha Satoshi 東京理科大学, 研究推進機構生命医科学研究所, 准教授 (00447385)
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| Research Collaborator |
Shichino Shigeyuki
Matsushima Kouji
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | 造血幹細胞ニッチ / T細胞 / 線維化 / GVHD / 同種造血幹細胞移植 / PDGF / 疾患モデル動物 / 移植免疫 |
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| Outline of Final Research Achievements |
We investigated the molecular and cellular mechanisms of chronic GVHD-associated impairments in bone marrow (BM) mesenchymal cells to establish the bases for novel prevention and therapy for allo-HSCT. In a murine chronic GVHD model, we found the development of broad suppression of hematopoiesis and BM fibrosis. PDGF and CTGF signaling are involved in the activation of Nf-kb and Stat pathway, and inhibition of PDGF signaling suppressed the BM fibrosis. Early administration of anti-CD4 mAb prevented BM failure. These findings may provide a preventive and therapeutic clue to improve the survival and QOL after allo-HSCT.
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| Academic Significance and Societal Importance of the Research Achievements |
これまでallo-HSCTに伴う免疫再構築不全の克服を目指す多くの研究は、GVHDによる胸腺障害に着目し、これを予防・治療するものがほとんどであった。我々は、急性GVHDモデルの解析から見出した新たな概念である骨髄GVHD、すなわち骨髄造血ニッチ障害によるリンパ球産生の抑制が、胸腺におけるT細胞産生抑制の上流で免疫再構築を障害していることを示してきた。本研究成果は、慢性GVHDにおける骨髄造血ニッチ障害の分子・細胞機序の一端を明らかにしたものであり、国際的にも極めて独創性の高い研究と言える。社会的にも、all-HSCT後に遷延する免疫不全を予防出来れば、生命予後とQOLの改善が期待できる。
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Report
(4 results)
Research Products
(39 results)
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[Journal Article] Transcriptome network analysis identifies protective role of the LXR/SREBP-1c axis in murine pulmonary fibrosis.2019
Author(s)
Shichino S, Ueha S, Hashimoto S, Otsuji M, Abe J, Tsukui T, Deshimaru S, Nakajima T, Kosugi-Kanaya M, Shand FH, Inagaki Y, Shimano H, Matsushima K.
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Journal Title
JCI Insight
Volume: 4(1)
Pages: 122163-122163
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Increased diversity with reduced "diversity evenness" of tumor infiltrating T-cells for the successful cancer immunotherapy.2018
Author(s)
Hosoi A, Takeda K, Nagaoka K, Iino T, Matsushita H, Ueha S, Aoki S, Matsushima K, Kubo M, Morikawa T, Kitaura K, Suzuki R, Kakimi K.
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Journal Title
SCIENITIFIC REPORTS.
Volume: 8
Pages: 1058-1058
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] The HIV co-receptor CCR5 regulates osteoclast function.2018
Author(s)
Lee JW, Hoshino A, Inoue K, Saitou T, Uehara S, Kobayashi Y, Ueha S, Matsushima K, Yamaguchi A, Imai Y, Iimura T.
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Journal Title
Nature communications
Volume: 8
Pages: 2226-2226
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Long-Lasting Graft-Derived Donor T Cells Contribute to the Pathogenesis of Chronic Graft-versus-Host Disease in Mice.2017
Author(s)
Kosugi-Kanaya M, Ueha S, Abe J, Shichino S, Shand FHW, Morikawa T, Kurachi M, Shono Y, Sudo N, Yamashita A, Suenaga F, Yokoyama A, Yong W, Imamura M, Teshima T, Matsushima K.
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Journal Title
Front Immunol
Volume: 8
Pages: 1842-1842
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Presentation] 肺線維症における細胞動態2016
Author(s)
上羽悟史、津久井達哉、七野成之、松島 綱治
Organizer
第40回日本リンパ学会総会
Place of Presentation
東京都（東京大学伊藤国際学術研究センター）
Year and Date
2016-06-24
Related Report
Invited
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