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A novel therapeutic strategy targeting HMGB1 isoforms in sepsis

Research Project

Project/Area Number 18H02904
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 55060:Emergency medicine-related
Research InstitutionKagoshima University

Principal Investigator

ITO Takashi  鹿児島大学, 医歯学総合研究科, 特任准教授 (20381171)

Co-Investigator(Kenkyū-buntansha) 丸山 征郎  鹿児島大学, 医歯学総合研究科, 特任教授 (20082282)
垣花 泰之  鹿児島大学, 医歯学域医学系, 教授 (20264426)
Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000)
Fiscal Year 2020: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2019: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
Fiscal Year 2018: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000)
Keywords敗血症 / 核内タンパク質 / DAMPs / アイソフォーム / 抗体 / トロンボモジュリン / 播種性血管内凝固(DIC) / HMGB1 / 治療 / 診断 / メディエーター / 組織損傷
Outline of Final Research Achievements

During sepsis, high mobility group box 1 protein (HMGB1) can be released from the cellular nucleus to the extracellular space. Extracellular HMGB1 acts as a signal of tissue damage and promotes not only inflammatory responses but also tissue regeneration. Recent studies have suggested that disulfide HMGB1 promotes inflammation whereas all-thiol HMGB1 promotes tissue regeneration. However, to date, there is no reliable way to differentially target these HMGB1 subtypes. In this research project, we have identified monoclonal antibodies that can discriminate between inactive HMGB1 and active HMGB1. We have also obtained a neutralizing antibody against HMGB1 that shows a significant survival benefit over the control antibody in mice with cecal ligation and puncture-induced sepsis. These antibodies may be useful for the in-depth analysis of HMGB1-induced pathogenicity as well as HMGB1-targeting therapy.

Academic Significance and Societal Importance of the Research Achievements

本邦では敗血症によって年間およそ10万人が命を落としていると推定されている。早期診断と集中治療によって生存率の改善が期待できるが、敗血症に対する特異的な治療法は確立されていない。細胞外に放出された核内タンパク質HMGB1は、有望な治療標的と考えられていたが、良い働きと悪い働きを併せ持ったタンパク質であるが故に、これまで十分な有用性が発揮されずにいた。本研究において、良い働きをするHMGB1と悪い働きをするHMGB1を区別しうるモノクローナル抗体を獲得できたことにより、敗血症の病態把握と新規治療戦略構築が進み、敗血症の生存率改善に寄与できる可能性が考えられる。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Annual Research Report
  • 2018 Annual Research Report

Research Products

(25 results)

All 2021 2020 2019 2018

All Journal Article (11 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 11 results,  Open Access: 11 results) Presentation (12 results) (of which Int'l Joint Research: 3 results,  Invited: 3 results) Book (2 results)

  • [Journal Article] Endotheliopathy in septic conditions: mechanistic insight into intravascular coagulation2021

    • Author(s)
      Ito Takashi、Kakuuchi Midori、Maruyama Ikuro
    • Journal Title

      Critical Care

      Volume: 25 Pages: 95-95

    • DOI

      10.1186/s13054-021-03524-6

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Attempt to Develop Rat Disseminated Intravascular Coagulation Model Using Yamakagashi (Rhabdophis tigrinus) Venom Injection2021

    • Author(s)
      Yamamoto Akihiko、Ito Takashi、Hifumi Toru
    • Journal Title

      Toxins

      Volume: 13 Pages: 160-160

    • DOI

      10.3390/toxins13020160

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Recombinant thrombomodulin alleviates oxidative stress without compromising host resistance to infection in rats infected with methicillin-resistant Staphylococcus aureus2020

    • Author(s)
      Ito Takashi、Shrestha Binita、Kakihana Yasuyuki、Maruyama Ikuro
    • Journal Title

      Scientific Reports

      Volume: 10 Pages: 17413-17413

    • DOI

      10.1038/s41598-020-74529-4

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Effects of thrombomodulin alfa on hemostatic parameters in disseminated intravascular coagulation: Post hoc analysis of a phase 3 randomized controlled trial2020

    • Author(s)
      Ito Takashi、Maruyama Ikuro、Shimazaki Shuji、Yamamoto Yasuhiro、Aikawa Naoki、Hirayama Akio、Honda Goichi、Saito Hidehiko
    • Journal Title

      Research and Practice in Thrombosis and Haemostasis

      Volume: 4 Pages: 1141-1149

    • DOI

      10.1002/rth2.12419

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Serum histone H3 levels and platelet counts are potential markers for coagulopathy with high risk of death in septic patients: a single-center observational study2019

    • Author(s)
      Ito Takashi、Totoki Takaaki、Yokoyama Yayoi、Yasuda Tomotsugu、Furubeppu Hiroaki、Yamada Shingo、Maruyama Ikuro、Kakihana Yasuyuki
    • Journal Title

      J Intensive Care.

      Volume: 7 Pages: 63-63

    • DOI

      10.1186/s40560-019-0420-2

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Thrombomodulin in disseminated intravascular coagulation and other critical conditions-a multi-faceted anticoagulant protein with therapeutic potential2019

    • Author(s)
      Ito T, Thachil J, Asakura H, Levy JH, Iba T.
    • Journal Title

      Crit Care.

      Volume: 23 Pages: 280-280

    • DOI

      10.1186/s13054-019-2552-0

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Recombinant Thrombomodulin Suppresses Histone-Induced Neutrophil Extracellular Trap Formation2019

    • Author(s)
      Shrestha Binita、Ito Takashi、Kakuuchi Midori、Totoki Takaaki、Nagasato Tomoka、Yamamoto Mika、Maruyama Ikuro
    • Journal Title

      Front Immunol.

      Volume: 10 Pages: 2535-2535

    • DOI

      10.3389/fimmu.2019.02535

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Fulminant myocarditis associated with severe fever with thrombocytopenia syndrome: a case report.2019

    • Author(s)
      Miyamoto S, Ito T, Terada S, Eguchi T, Furubeppu H, Kawamura H, Yasuda T, Kakihana Y.
    • Journal Title

      BMC Infectious Diseases

      Volume: 19 Pages: 266-266

    • DOI

      10.1186/s12879-019-3904-8

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Circulating histone H3 levels in septic patients are associated with coagulopathy, multiple organ failure, and death: a single-center observational study2019

    • Author(s)
      Yokoyama Yayoi、Ito Takashi、Yasuda Tomotsugu、Furubeppu Hiroaki、Kamikokuryo Chinatsu、Yamada Shingo、Maruyama Ikuro、Kakihana Yasuyuki
    • Journal Title

      Thromb J.

      Volume: 17 Pages: 1-1

    • DOI

      10.1186/s12959-018-0190-4

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Loss of Endogenous HMGB2 Promotes Cardiac Dysfunction and Pressure Overload-Induced Heart Failure in Mice2019

    • Author(s)
      Sato M, Miyata K, Tian Z, Kadomatsu T, Ujihara Y, Morinaga J, Horiguchi H, Endo M, Zhao J, Zhu S, Sugizaki T, Igata K, Muramatsu M, Minami T, Ito T, and OikeY
    • Journal Title

      Circ J

      Volume: 83 Issue: 2 Pages: 335-340

    • DOI

      10.1253/circj.cj-18-0925

      10.1253/circj.CJ-18-0925

    • NAID

      130007557092

    • ISSN
      1346-9843, 1347-4820
    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Circulating histone H3 levels are increased in septic mice in a neutrophil-dependent manner: preclinical evaluation of a novel sandwich ELISA for histone H32018

    • Author(s)
      Ito Takashi、Nakahara Mayumi、Masuda Yoshiki、Ono Sachie、Yamada Shingo、Ishikura Hiroyasu、Imaizumi Hitoshi、Kamikokuryo Chinatsu、Kakihana Yasuyuki、Maruyama Ikuro
    • Journal Title

      Journal of Intensive Care

      Volume: 6 Pages: 79-79

    • DOI

      10.1186/s40560-018-0348-y

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] 救急疾患に伴う凝固線溶異常のオーバービュー2020

    • Author(s)
      伊藤 隆史
    • Organizer
      第42回日本血栓止血学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Endotheliopathy in septic conditions2020

    • Author(s)
      Ito Takashi
    • Organizer
      International Society on Thrombosis and Haemostasis 2020 Virtual Congress
    • Related Report
      2020 Annual Research Report
  • [Presentation] 好中球の生理と病理と臓器障害2020

    • Author(s)
      伊藤 隆史
    • Organizer
      第48回日本救急医学会総会・学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] ダメージ関連分子パターン(DAMPs)の解析と応用展開2020

    • Author(s)
      伊藤 隆史
    • Organizer
      第67回日本臨床検査医学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 目で視て考える侵襲に対する宿主応答と臓器障害2020

    • Author(s)
      伊藤隆史
    • Organizer
      第47回日本集中治療医学会学術集会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] Mechanism-based anticoagulant strategy in sepsis-associated DIC2020

    • Author(s)
      伊藤隆史
    • Organizer
      第47回日本集中治療医学会学術集会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] Circulating histone H3 as an indicator/inducer of DIC and organ failure2019

    • Author(s)
      Takashi Ito
    • Organizer
      9th International DAMPs and Alarmins Symposium
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Plasma activated protein C activity in the presence of recombinant thrombomodulin in vivo and in vitro2019

    • Author(s)
      Takashi Ito
    • Organizer
      ISTH 2019: The XXVII Congress of the International Society on Thrombosis and Haemostasis
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 図解 敗血症学2019

    • Author(s)
      伊藤隆史
    • Organizer
      第120回 近畿救急医学研究会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 敗血症病態における血栓形成の光と影2019

    • Author(s)
      伊藤隆史
    • Organizer
      第46回日本集中治療医学会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 凝固/抗凝固反応はどこで起きているのか cell-based model の紹介2018

    • Author(s)
      伊藤隆史
    • Organizer
      第80回日本血液学会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Leukocyte-derived extracellular DNA as an underlying cause of extracorporeal circuit obstruction2018

    • Author(s)
      Takashi Ito
    • Organizer
      International Society on Thrombosis and Haemostasis SSC meeting 2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Book] New Strategy! 超微形態生理学 ICU輸液がみえるグリコカリックス×アトラス2020

    • Author(s)
      伊藤 隆史
    • Total Pages
      268
    • Publisher
      メジカルビュー社
    • ISBN
      9784758317818
    • Related Report
      2020 Annual Research Report
  • [Book] ファーマナビゲーター  DIC編 改訂版2019

    • Author(s)
      伊藤隆史
    • Total Pages
      435
    • Publisher
      メディカルレビュー社
    • ISBN
      9784779222337
    • Related Report
      2019 Annual Research Report

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Published: 2018-04-23   Modified: 2022-01-27  

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