Development of a new therapeutic method for radiation-induced gastrointestinal syndrome targeting the innate immune system
| Project/Area Number |
17H04257
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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 |
Radiation science
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| Research Institution | Osaka City University (2018-2019)
Chiba University (2017) |
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Principal Investigator |
Uematsu Satoshi 大阪市立大学, 大学院医学研究科, 教授 (50379088)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥16,640,000 (Direct Cost: ¥12,800,000、Indirect Cost: ¥3,840,000)
Fiscal Year 2019: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2018: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2017: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
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| Keywords | 放射線誘導性腸線維症 / 好酸球 / 抗体療法 / 電離放射線 / 粘膜傷害 / 粘膜ワクチン / IgA / 腸内細菌 / 放射線 / 粘膜障害 / 線維化 / 自然免疫 / 放射線腸炎 |
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| Outline of Final Research Achievements |
Radiation-induced intestinal fibrosis (RIF) is a serious complication after abdominal radiotherapy. Abdominal irradiation induced fibrosis of the submucosa associated with the excessive accumulation of eosinophils. Eosinophil-deficiency markedly ameliorated submucosal fibrosis post-irradiation. Irradiation elevated extracellular adenosine triphosphate levels, which in turned induced CCL11 and GM-CSF expression by submucosal pericryptal α-SMA+ cells that attracted and activated eosinophils, respectively. TGF-β from GM-CSF-stimulated eosinophils promoted collagen expression by α-SMA+ cells. Treatment with a newly developed IL-5 receptor alpha-targeting antibody, analogous to the human agent benralizumab, depleted intestinal eosinophils and suppressed radiation-induced submucosal fibrosis effectively. Collectively, we identified eosinophils as a crucial factor in the pathogenesis of RIF and showed a new therapeutic strategy for RIF targeting on eosinophils.
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| Academic Significance and Societal Importance of the Research Achievements |
消化管は放射線に対する感受性が非常に高く、癌の放射線治療において高線量の放射線に被曝すると、急性期から晩期に渡って多彩な障害が引き起こされ、効果的な予防・治療法の確立が強く求められている。特に、晩期の腸管の線維化は患者のQOLを著しく低下させるが、治療法がなかった。今回、好酸球による病態形成を明らかにし、好酸球除去抗体が有効な治療法となることをマウスで示したことは非常に大きな成果である。この抗体の人アナログは既に重症気管支喘息で、実用化されている。今後、RIFの新しい治療法が確立するのもそう遠くないと考える。学術的だけでなく、社会的にも重要な成果を得ることができた。
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Report
(4 results)
Research Products
(48 results)
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[Journal Article] Microsomal prostaglandin E synthase-1 promotes lung metastasis via SDF-1/CXCR4-mediated recruitment of CD11b+Gr1+MDSCs from bone marrow2020
Author(s)
Takahashi R, Amano H, Ito Y, Eshima K, Satoh T, Iwamura M, Nakamura M, Kitasato H, Uematsu S, Raouf J, Jakobsson PJ, Akira S, Majima M
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Journal Title
Biomedicine & Pharmacotherapy
Volume: 121
Pages: 109581-109581
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Intestinal CD103(+)CD11b(+)cDC2 Conventional Dendritic Cells Are Required for Primary CD4(+) T and B Cell Responses to Soluble Flagellin.2018
Author(s)
Flores-Langarica A, Cook C, Muller Luda K, Persson EK, Marshall JL, Beristain-Covarrubias N, Yam-Puc JC, Dahlgren M, Persson JJ, Uematsu S, Akira S, Henderson IR, Lindbom BJ, Agace W, Cunningham AF.
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Journal Title
Front Immunol.
Volume: 9
Pages: 2409-2409
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] DUSP10 constrains innate IL-33-mediated cytokine production in ST2hi memory-type pathogenic Th2 cells2018
Author(s)
Yamamoto, T., Endo, Y., Onodera, A., Hirahara, K., Asou, H., Nakajima, T., Kanno, T., Ouchi, Y., Uematsu, S., Nishimasu, H., Nureki, O., Tumes, D. J., Shimojo, N., and Nakayama, T.
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Journal Title
Nature Communications
Volume: 9
Issue: 1
Pages: 4231-4231
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Inhibition of microsomal prostaglandin E synthase-1 facilitates liver repair after hepatic injury in mice.2018
Author(s)
Nishizawa N, Ito Y, Eshima K, Ohkubo H, Kojo K, Inoue T, Raouf J, Jakobsson PJ, Uematsu S, Akira S, Narumiya S, Watanabe M, Majima M.
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Journal Title
J Hepatol.
Volume: S0168-8278(18)
Issue: 1
Pages: 30126-30130
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Generation of tumor antigen-specific murine CD8+ T cells with enhanced anti-tumor activity via highly efficient CRISPR/Cas9 genome editing2018
Author(s)
Ouchi Y, Patil A, Tamura Y, Nishimasu H, Negishi A, Paul SK, Takemura N, Satoh T, Kimura Y, Kurachi M, Nureki O, Nakai K, Kiyono H, Uematsu S.
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Journal Title
International Immunology
Volume: 30
Issue: 4
Pages: 141-154
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Eosinophil depletion suppresses radiation-induced small intestinal fibrosis.2018
Author(s)
Takemura N, Kurashima Y, Mori Y, Okada K, Ogino T, Osawa H, Matsuno H, Aayam L, Kaneto S, Park EJ, Sato S, Matsunaga K, Tamura Y, Ouchi Y, Kumagai Y, Kobayashi D, Suzuki Y, Yoshioka Y, Nishimura J, Mori M, Ishii KJ, Rothenberg ME, Kiyono H, Akira S, Uematsu S.
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Journal Title
Sci Transl Med.
Volume: --
Issue: 429
Pages: 264-273
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] L, Bannai E, Yoshikawa N, Kimura Y, Satoh T, Uematsu S, Tanaka H, Yamamoto K. Intestinal microbiota link lymphopenia to murine autoimmunity via PD-1(+)CXCR5(-/dim) B-helper T cell induction.2017
Author(s)
Eri T, Kawahata K, Kanzaki T, Imamura M, Michishita K, Akahira L, Bannai E, Yoshikawa N, Kimura Y, Satoh T, Uematsu S, Tanaka H, Yamamoto K.
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Journal Title
Scientific Reports
Volume: 7
Issue: 1
Pages: 1-17
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Herpes simplex virus-1 evasion of CD8+ T cell accumulation contributes to viral encephalitis.2017
Author(s)
Koyanagi N, Imai T, Shindo K, Sato A, Fujii W, Ichinohe T, Takemura N, Kakuta S, Uematsu S, Kiyono H, Maruzuru Y, Arii J, Kato A, Kawaguchi Y.
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Journal Title
J Clin Invest.
Volume: 127
Issue: 10
Pages: 3784-3795
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] A Refined Culture System for Human Induced Pluripotent Stem Cell-Derived Intestinal Epithelial Organoids.2017
Author(s)
Takahashi Y, Sato S, Kurashima Y, Yamamoto T, Kurokawa S, Yuki Y, Takemura N, Uematsu S, Lai CY, Otsu M, Matsuno H, Osawa H, Mizushima T, Nishimura J, Hayashi M, Yamaguchi T, Kiyono H.
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Journal Title
Stem Cell Reports.
Volume: --
Issue: 1
Pages: 314-328
DOI
Related Report
Peer Reviewed / Open Access
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