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Elucidation of the regulatory mechanisms of inflammation and immune responses by damage-associated molecules

Research Project

Project/Area Number 20H00504
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Review Section Medium-sized Section 49:Pathology, infection/immunology, and related fields
Research InstitutionThe University of Tokyo

Principal Investigator

Taniguchi Tadatsugu  東京大学, 先端科学技術研究センター, 名誉教授 (50133616)

Co-Investigator(Kenkyū-buntansha) 半谷 匠  東京大学, 先端科学技術研究センター, 客員研究員 (50785350)
柳井 秀元  東京大学, 先端科学技術研究センター, 特任准教授 (70431765)
Project Period (FY) 2020-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥43,940,000 (Direct Cost: ¥33,800,000、Indirect Cost: ¥10,140,000)
Fiscal Year 2023: ¥9,620,000 (Direct Cost: ¥7,400,000、Indirect Cost: ¥2,220,000)
Fiscal Year 2022: ¥10,010,000 (Direct Cost: ¥7,700,000、Indirect Cost: ¥2,310,000)
Fiscal Year 2021: ¥11,310,000 (Direct Cost: ¥8,700,000、Indirect Cost: ¥2,610,000)
Fiscal Year 2020: ¥13,000,000 (Direct Cost: ¥10,000,000、Indirect Cost: ¥3,000,000)
Keywords免疫シグナル伝達 / 炎症 / 自然免疫受容体 / HMGB1 / TCTP / U11snRNA / 腫瘍免疫 / 免疫原性核酸 / 恒常性維持 / がん / DAMPs / 核酸 / サイトカイン / 自己免疫疾患 / DAMP / 疾患
Outline of Research at the Start

死細胞やストレスを受けた細胞から放出される自己分子群(DAMPs)が炎症・免疫系をどのように調節するか、解明を目指す。具体的には代表的なDAMPであるHMGB1の機能解析を推進するとともに、U11 snRNAや新規に見出しつつあるDAMP分子群による炎症・免疫応答の制御機構の解明を行う。本研究において、DAMP分子群を介した炎症・免疫反応とそれらが関与する疾患の包括的理解を目指す。

Outline of Final Research Achievements

In this study, we studied the mechanisms of regulation of inflammatory and immune responses by self-derived molecules called DAMPs (damage-associated molecular patterns). DAMPs are released from damaged or dead cells, thereby contributing to development and/or exacerbating of diseases such as cancer. We analyzed the function of HMGB1 and adduced evidence that the lack of HMGB1 results in exacerbation of sepsis in mice. We newly identified TCTP and spermidine as self-derived molecules that impinge on anti-tumor immune responses and elucidated their mechanisms of action. We also developed the neutralizing antibody for TCTP, and found that the antibody treatment enhances anti-tumor immune responses and suppresses tumor growth.

Academic Significance and Societal Importance of the Research Achievements

本研究において、TCTPやスペルミジンなど、免疫応答の制御に関与する死細胞由来分子を同定した。また細胞外TCTPの作用を阻害することで腫瘍免疫の活性化を増強させ、病態を抑制することが可能であることも示された。HMGB1やU11 snRNAなどについてもさらに検討を加えていくことで、死細胞由来分子による免疫制御機構の全体像の解明につなげていきたい。また、本研究をさらに発展させていくことで、新たな病態抑制法の開発が進むことも期待される。

Report

(6 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Annual Research Report
  • 2021 Annual Research Report
  • 2020 Comments on the Screening Results   Annual Research Report
  • Research Products

    (27 results)

All 2023 2022 2021 2020 Other

All Journal Article (11 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 11 results,  Open Access: 8 results) Presentation (14 results) (of which Int'l Joint Research: 6 results,  Invited: 14 results) Remarks (1 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] Tumor cell derived spermidine is an oncometabolite that suppresses TCR clustering for intratumoral CD8+ T cell activation2023

    • Author(s)
      Hibino S, Eto S, Hangai S, Endo K, Ashitani S, Sugaya M, Osawa T, Soga T, Taniguchi T and Yanai H
    • Journal Title

      PNAS

      Volume: 120 (24) Issue: 24

    • DOI

      10.1073/pnas.2305245120

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Diet-mediated constitutive induction of novel IL4+ ILC2 cells maintains intestinal homeostasis in mice2023

    • Author(s)
      Cui Wanlin, Nagano Yuji, Hatakeyama Masanori, Honda Kenya , et al.
    • Journal Title

      Journal of Experimental Medicine

      Volume: - Issue: 8

    • DOI

      10.1084/jem.20221773

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Potential of HMGB-inhibitory oligodeoxynucleotide ISM ODN to neutrophil recruitment in mouse model of hepatitis2022

    • Author(s)
      Inoue Asuka、Chiba Shiho、Eto Shotaro、Taniguchi Tadatsugu、Yanai Hideyuki
    • Journal Title

      Genes to Cells

      Volume: 28 Issue: 3 Pages: 202-210

    • DOI

      10.1111/gtc.13002

    • Related Report
      2023 Annual Research Report 2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Identification and characterization of a novel Enterococcus bacteriophage with potential to ameliorate murine colitis2021

    • Author(s)
      Nishio Junko、Negishi Hideo、Yasui-Kato Mika、Miki Shoji、Miyanaga Kazuhiko、Aoki Kotaro、Mizusawa Takuma、Ueno Masami、Ainai Akira、Muratani Masafumi、Hangai Sho、Yanai Hideyuki、Hasegawa Hideki、Ishii Yoshikazu、Tanji Yasunori、Taniguchi Tadatsugu
    • Journal Title

      Scientific Reports

      Volume: 11 Issue: 1 Pages: 20231-20231

    • DOI

      10.1038/s41598-021-99602-4

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Irf5 siRNA-loaded biodegradable lipid nanoparticles ameliorate concanavalin A-induced liver injury2021

    • Author(s)
      Kawase Wataru、Kurotaki Daisuke、Suzuki Yuta、Ishihara Hiroshi、Ban Tatsuma、Sato Go R.、Ichikawa Juri、Yanai Hideyuki、Taniguchi Tadatsugu、Tsukahara Kappei、Tamura Tomohiko
    • Journal Title

      Molecular Therapy - Nucleic Acids

      Volume: 25 Pages: 708-715

    • DOI

      10.1016/j.omtn.2021.08.023

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Damage-associated molecular patterns and Toll-like receptors in the tumor immune microenvironment2021

    • Author(s)
      Yanai Hideyuki、Hangai Sho、Taniguchi Tadatsugu
    • Journal Title

      International Immunology

      Volume: 33 Issue: 12 Pages: 841-846

    • DOI

      10.1093/intimm/dxab050

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Genetic and chemical inhibition of IRF5 suppresses pre-existing mouse lupus-like disease2021

    • Author(s)
      Ban T, Kikuchi M, Sato GR, Manabe A, Tagata N, Harita K, Nishiyama A, Nishimura K, Yoshimi R, Kirino Y, Yanai H, Matsumoto Y, Suzuki S, Hihara H, Ito M, Tsukahara K, Yoshimatsu K, Yamamoto T, Taniguchi T, Nakajima H, Ito S, Tamura T
    • Journal Title

      Nature Communications

      Volume: 12 Issue: 1 Pages: 4379-4379

    • DOI

      10.1038/s41467-021-24609-4

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Orchestration of myeloid-derived suppressor cells in the tumor microenvironment by ubiquitous cellular protein TCTP released by tumor cells2021

    • Author(s)
      Hangai Sho、Kawamura Takeshi、Kimura Yoshitaka、Chang Ching-Yun、Hibino Sana、Yamamoto Daisuke、Nakai Yousuke、Tateishi Ryosuke、Oshima Masanobu、Oshima Hiroko、Kodama Tatsuhiko、Moriya Kyoji、Koike Kazuhiko、Yanai Hideyuki、Taniguchi Tadatsugu
    • Journal Title

      Nature Immunology

      Volume: 22 Issue: 8 Pages: 947-957

    • DOI

      10.1038/s41590-021-00967-5

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Signal transducing innate receptors in tumor immunity2021

    • Author(s)
      Hangai Sho、Kimura Yoshitaka、Taniguchi Tadatsugu、Yanai Hideyuki
    • Journal Title

      Cancer Science

      Volume: - Issue: 7 Pages: 2578-2591

    • DOI

      10.1111/cas.14848

    • Related Report
      2021 Annual Research Report 2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] HMGB1-mediated chromatin remodeling attenuates Il24 gene expression for the protection from allergic contact dermatitis2021

    • Author(s)
      Senda N, Yanai H, Hibino S, Li L, Mizushima Y, Miyagaki T, Saeki M, Kishi Y, Hangai S, Nishio J, Sugaya M, Taniguchi T, Sato S
    • Journal Title

      Proc Natl Acad Sci U S A

      Volume: 118 Issue: 1

    • DOI

      10.1073/pnas.2022343118

    • Related Report
      2021 Annual Research Report 2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The impact of damage-associated molecules released from canine tumor cells on gene expression in macrophages2021

    • Author(s)
      Eto Shotaro、Yanai Hideyuki、Hangai Sho、Kato Daiki、Nishimura Ryohei、Nakagawa Takayuki
    • Journal Title

      Scientific Reports

      Volume: 11 Issue: 1 Pages: 8525-8525

    • DOI

      10.1038/s41598-021-87979-1

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] Damage-associated molecular patterns and toll-like receptors in the tumor immune microenvironment2023

    • Author(s)
      谷口維紹
    • Organizer
      第35回国際ヒトパピローマウイルス学会
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Distinguished Investigator Seminar2023

    • Author(s)
      谷口維紹
    • Organizer
      IFNs/IRFs and DAMPs in tumor immunology
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] Damage-associated molecular patterns in the tumor immune microenvironment2023

    • Author(s)
      谷口維紹
    • Organizer
      European Cell Death Organization (ECDO) and the European Academy of Tumor Immunology (EATI)
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Interferons, p53/MDM2 and DAMPs; discovering the underpinnings of immunity2023

    • Author(s)
      谷口維紹
    • Organizer
      第10回国際MDM2学会
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Regulation of Tumor Immune Microenvironment by Damage-associated Molecular Patterns (DAMPs): Therapeutic Implications2022

    • Author(s)
      Tadatsugu Taniguchi
    • Organizer
      FOCIS2021
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 炎症・免疫系における自己由来分子2022

    • Author(s)
      谷口維紹
    • Organizer
      第72回日本体質医学会総会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 細胞死による炎症・免疫反応を標的とした制がん2022

    • Author(s)
      柳井秀元
    • Organizer
      日本がん分子標的治療学会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] がん死細胞由来分子による腫瘍中の免疫微小環境制御の解析2022

    • Author(s)
      柳井秀元
    • Organizer
      日本炎症・再生医学会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] TCTPによる免疫抑制とがん増殖機構2022

    • Author(s)
      柳井秀元
    • Organizer
      日本Cell Death学会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] Modulation of tumor immune responses by dead cell-derived molecules2022

    • Author(s)
      Hideyuki Yanai
    • Organizer
      Asian Oncology Society AOS2022
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Regulation of tumor immune microenvironment by Damage-associated molecular Patterns (DAMPs): Therapeutic implications2021

    • Author(s)
      Tadatsugu Taniguchi
    • Organizer
      FOCIS
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] がん細胞由来の新規調節分子;がんの微小環境を標的とした治療法確立に向けて2021

    • Author(s)
      谷口維紹
    • Organizer
      日本がん免疫学会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] がんと免疫系の相互作用;死細胞由来分子によるがんの免疫微小環境の調節機構2020

    • Author(s)
      谷口維紹
    • Organizer
      第24回日本がん免疫学会総会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] 炎症と免疫老化における細胞障害関連分子 (DAMPs) の役割の解析2020

    • Author(s)
      柳井秀元
    • Organizer
      第20回抗加齢医学会総会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Remarks]

    • URL

      http://mol-immu.umin.jp/

    • Related Report
      2022 Annual Research Report
  • [Patent(Industrial Property Rights)] がん免疫微小環境の調節物質およびそれによる予防・診断・治療的利用2020

    • Inventor(s)
      谷口維紹、半谷匠、柳井秀元
    • Industrial Property Rights Holder
      谷口維紹、半谷匠、柳井秀元
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2020-147222
    • Filing Date
      2020
    • Related Report
      2020 Annual Research Report

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Published: 2020-04-28   Modified: 2025-01-30  

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