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Search for new treatments for influenza associated encephalopathy targeting innate immune mediators

Research Project

Project/Area Number 19K08278
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 52050:Embryonic medicine and pediatrics-related
Research InstitutionOkayama University

Principal Investigator

TSUGE MITSURU  岡山大学, 医歯薬学域, 講師 (80625004)

Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2021: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords脳血管内皮細胞 / インフルエンザ脳症 / 脳浮腫 / 自然免疫 / サイトカイン / タイトジャンクション / 腫瘍壊死因子-α / 炎症性サイトカイン / HMGB-1 / 血管透過性 / マクロファージ / IL-6 / VEカドヘリン / ストレスファイバー / COX-2 / 血管内皮細胞 / 末梢血単核球
Outline of Research at the Start

インフルエンザ脳症は小児に多く発症し、けいれんや意識障害を認め、時に脳浮腫や後遺症を残す病気である。近年、自然炎症メディエータの一つであるhigh mobility group box 1(HMGB-1)が後遺症を認めた患者の血液中で増加していることや、インフルエンザ脳症をモデルとした動物実験でHMGB-1の効果を抑える抗体を投与すると、脳の血管のバリア機能が障害が軽減することが明らかとなった。HMGB-1に対する抗体がどのようにしてインフルエンザ脳症の病態を改善するのかを明らかにするために、ヒトの脳の血管内皮細胞や動物モデル、インフルエンザ脳症に罹患した児の血液細胞を用いて検討する。

Outline of Final Research Achievements

We investigated whether high mobility group box-1 (HMGB-1) monoclonal antibody could suppress the increase in vascular permeability of human primary cerebral vascular endothelial cells by tumor necrosis factor (TNF-α). After TNF-α stimulation, vascular permeability was significantly enhanced, and cell spindle-like deformation, increased intercellular space, increased F-actin formation, and decreased amount of VE-cadherin protein, which is a tight junction molecule, were observed. In the presence of anti-HMGB-1 antibody, vascular hyperpermeability was significantly suppressed, and the increase in intercellular space and the decrease in VE-cadherin protein were significantly suppressed. The concentrations of IL-6 and IP-10, which are inflammatory cytokines in the supernatant, increased by TNF-α stimulation were significantly suppressed in the presence of anti-HMGB-1 antibody.

Academic Significance and Societal Importance of the Research Achievements

インフルエンザ脳症における脳浮腫・脳血管透過性亢進のメカニズムと自然免疫分子であるHMGB-1分子の関与について検討した。HMGB-1分子を中和するモノクローナル抗体によって、サイトカインによる脳血管内皮細胞の血管透過性亢進や細胞形態の変化、細胞間にあるタイトジャンクション分子と呼ばれる蛋白の減少を抑制することを明らかにした。インフルエンザ脳症の新規治療として抗HMGB-1モノクローナル抗体の有効性を説明しうる研究成果を得た。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (11 results)

All 2022 2021 2020 2019

All Journal Article (7 results) (of which Peer Reviewed: 7 results,  Open Access: 7 results) Presentation (3 results) Book (1 results)

  • [Journal Article] Severe pediatric asthma with a poor response to omalizumab: a report of three cases and three-dimensional bronchial wall analysis2022

    • Author(s)
      Tsuge Mitsuru、Ikeda Masanori、Kondo Yoichi、Tsukahara Hirokazu
    • Journal Title

      Journal of International Medical Research

      Volume: 50 Issue: 1 Pages: 1-10

    • DOI

      10.1177/03000605211070492

    • NAID

      120007183226

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] COVID-19 in Okayama Prefecture: Looking back and looking forward2021

    • Author(s)
      Tsukahara Hirokazu、Higashionna Tsukasa、Tsuge Mitsuru、Miyamura Junko、Kusano Nobuchika
    • Journal Title

      Global Health & Medicine

      Volume: 3 Issue: 2 Pages: 102-106

    • DOI

      10.35772/ghm.2020.01104

    • NAID

      130008036363

    • ISSN
      2434-9186, 2434-9194
    • Year and Date
      2021-04-30
    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Current Insights into Atopic March2021

    • Author(s)
      Tsuge M, Ikeda M, Matsumoto N, Yorifuji T, Tsukahara H
    • Journal Title

      Children (Basel)

      Volume: 19;8(11) Issue: 11 Pages: 1067-1067

    • DOI

      10.3390/children8111067

    • NAID

      120007180266

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Reactive Oxygen Species and Antioxidative Defense in Chronic Obstructive Pulmonary Disease2021

    • Author(s)
      Taniguchi A, Tsuge M, Miyahara N, Tsukahara H
    • Journal Title

      Antioxidants (Basel)

      Volume: 28;10(10) Issue: 10 Pages: 1537-1537

    • DOI

      10.3390/antiox10101537

    • NAID

      120007170512

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Anaphylaxis after jellyfish ingestion with no history of stings: a pediatric case report2021

    • Author(s)
      Tsuge Mitsuru、Ikeda Masanori、Mitani Osamu、Yasui Masato、Tsukahara Hirokazu
    • Journal Title

      Allergy, Asthma & Clinical Immunology

      Volume: 17 Issue: 1 Pages: 99-99

    • DOI

      10.1186/s13223-021-00601-x

    • NAID

      120007161118

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Terry’s nails in an infant with liver cirrhosis2021

    • Author(s)
      Uda Kazuhiro、Tsuge Mitsuru、Shigehara Kenji、Yashiro Masato、Tsukahara Hirokazu
    • Journal Title

      Archives of Disease in Childhood

      Volume: 107 Issue: 5 Pages: 485-485

    • DOI

      10.1136/archdischild-2021-322953

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Anti-high mobility group box 1 monoclonal antibody suppressed hyper-permeability and cytokine production in human pulmonary endothelial cells infected with influenza A virus2021

    • Author(s)
      Namba T, Tsuge M, Yashiro M, Saito Y, Liu K, Nishibori M, Morishima T, Tsukahara H
    • Journal Title

      Inflamm Res

      Volume: 70(10-12) Issue: 10-12 Pages: 1101-1111

    • DOI

      10.1007/s00011-021-01496-5

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] インフルエンザA(H1N1)pdm09による急性呼吸窮迫症候群に対して体外式膜型人工肺とペラミビル・バロキサビルマルボキシル併用療法で改善した一例2020

    • Author(s)
      津下 充, 茂原 研司, 斎藤 有希惠, 八代 将登, 塚原 宏一
    • Organizer
      第52回日本小児感染症学会総会・学術集会
    • Related Report
      2020 Research-status Report
  • [Presentation] 肺血管内皮細胞を用いた重症インフルエンザ肺炎モデルの構築と high mobility group box 1抗体による肺血管透過性亢進の抑制効果2020

    • Author(s)
      難波貴弘, 津下充, 八代将登, 塚原宏一, 森島恒雄
    • Organizer
      第61回日本臨床ウイルス学会
    • Related Report
      2020 Research-status Report
  • [Presentation] ヒト脳血管内皮細胞を用いた高サイトカイン血症モデルにおけるhigh mobility group box-1抗体の血管透過性抑制効果2019

    • Author(s)
      津下 充,難波貴弘,西堀正洋,斎藤有希恵,八代将登,塚原宏一,森島恒雄
    • Organizer
      第51回日本小児感染症学会総会・学術集会
    • Related Report
      2019 Research-status Report
  • [Book] Influenza: Advances in Diagnosis and Management2020

    • Author(s)
      Tsuge M, Yashiro M, Ohno N, Tsukahara H, Fujita J
    • Total Pages
      229
    • Publisher
      Springer Nature
    • Related Report
      2020 Research-status Report

URL: 

Published: 2019-04-18   Modified: 2023-01-30  

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