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Evaluation of the importance of intracellular metabolism in individual differences in drug hypersensitivity using a mouse model of cutaneous adverse drug reaction

Research Project

Project/Area Number 21K15311
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 47060:Clinical pharmacy-related
Research InstitutionUniversity of Toyama

Principal Investigator

Susukida Takeshi  富山大学, 学術研究部薬学・和漢系, 助教 (50880689)

Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2023: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords薬物過敏症 / HLA / CD8陽性T細胞 / 細胞内エネルギー代謝 / 解糖系 / 免疫寛容 / 細胞内代謝
Outline of Research at the Start

薬物過敏症の個人差は遺伝的要因と環境要因に関連することが知られているが、遺伝的要因であるヒト白血球抗原(HLA)多型のみを考慮した場合、リスク薬物を完全に予測できないことが問題となっている。一方で、HLA多型の遺伝子導入マウスを用いた検討で、抗HIV薬アバカビルが惹起する薬物過敏症への免疫チェックポイント分子の関与がこれまでに明らかになり、本マウスが環境要因を探る薬疹モデルとなることが見出されている。本研究では「細胞内代謝環境の変化により免疫チェックポイント分子の発現量が制御される機構」に焦点を当て、薬物過敏症の個人差を左右する細胞内代謝環境の重要性について薬疹モデルマウスを用いて検証する。

Outline of Final Research Achievements

Drug hypersensitivity associated with specific human leukocyte antigen (HLA) allotype does not occur in all subjects of a given HLA model population, suggesting the difficulties to predict the onset risk without considering additional factors. In this study, we demonstrated that the expression level of Hk2 and glycolysis level in CD8+ T cells was upregulated in our mouse model of cutaneous adverse drug reaction. In addition, glycolysis inhibition by either glycolysis inhibitor treatment or dietary calorie restriction resulted in attenuation of drug hypersensitivity.

Academic Significance and Societal Importance of the Research Achievements

本研究によって薬物過敏症の個人差を生み出す免疫細胞内のエネルギー代謝環境の重要性が実証された。さらに、食事内容によって生体での栄養状態が異なる場合においても薬物過敏症発症の大小が決定づけられることが明らかとなり、食生活の違いが発症環境要因に位置付けられる可能性も示された。今後のさらなる研究の発展によって薬物過敏症の発症リスクの高い集団をより正確に見極められるようになることで、より安全な個別化医療の提供が実現可能となることが期待される。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • Research Products

    (19 results)

All 2024 2023 2022 2021 Other

All Journal Article (5 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 5 results,  Open Access: 4 results) Presentation (12 results) (of which Int'l Joint Research: 1 results) Remarks (2 results)

  • [Journal Article] HLA-B*57:01-dependent intracellular stress in keratinocytes triggers dermal hypersensitivity reactions to abacavir2024

    • Author(s)
      Kazaoka Akira、Fujimori Sota、Yamada Yushiro、Shirayanagi Tomohiro、Gao Yuying、Kuwahara Saki、Sakamoto Naoki、Susukida Takeshi、Aoki Shigeki、Ito Kousei
    • Journal Title

      PNAS Nexus

      Volume: 3 Issue: 4 Pages: 140-140

    • DOI

      10.1093/pnasnexus/pgae140

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Drug-induced altered self-presentation increases tumor immunogenicity2023

    • Author(s)
      Susukida Takeshi、Sasaki So-ichiro、Shirayanagi Tomohiro、Aoki Shigeki、Ito Kousei、Hayakawa Yoshihiro
    • Journal Title

      Biomedicine & Pharmacotherapy

      Volume: 165 Pages: 115241-115241

    • DOI

      10.1016/j.biopha.2023.115241

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Calorie Restriction Impairs Anti-Tumor Immune Responses in an Immunogenic Preclinical Cancer Model2023

    • Author(s)
      Dung Nguyen Tien、Susukida Takeshi、Ucche Sisca、He Ka、Sasaki So-ichiro、Hayashi Ryuji、Hayakawa Yoshihiro
    • Journal Title

      Nutrients

      Volume: 15 Issue: 16 Pages: 3638-3638

    • DOI

      10.3390/nu15163638

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Regulation of the immune tolerance system determines the susceptibility to HLA-mediated abacavir-induced skin toxicity2021

    • Author(s)
      Susukida Takeshi、Kuwahara Saki、Song Binbin、Kazaoka Akira、Aoki Shigeki、Ito Kousei
    • Journal Title

      Communications Biology

      Volume: 4 Issue: 1 Pages: 1137-1137

    • DOI

      10.1038/s42003-021-02657-2

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The PD1 inhibitory pathway and mature dendritic cells contribute to abacavir hypersensitivity in human leukocyte antigen transgenic PD1 knockout mice2021

    • Author(s)
      Song Binbin、Aoki Shigeki、Liu Cong、Susukida Takeshi、Kuwahara Saki、Ito Kousei
    • Journal Title

      Toxicology

      Volume: 463 Pages: 152971-152971

    • DOI

      10.1016/j.tox.2021.152971

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] 薬物過敏症発症におけるCD8+ T細胞の解糖系代謝の重要性2024

    • Author(s)
      薄田健史,孫雨晨, 青木重樹, 伊藤晃成, 早川芳弘
    • Organizer
      日本薬学会第144年会
    • Related Report
      2023 Annual Research Report
  • [Presentation] カロリー制限がHLA多型の関与する薬物毒性発症に及ぼす影響2023

    • Author(s)
      薄田健史, 青木重樹, 早川芳弘
    • Organizer
      第50回日本毒性学会学術年会
    • Related Report
      2023 Annual Research Report
  • [Presentation] HLA多型の関与する薬物過敏症の発症における解糖系代謝の重要性2023

    • Author(s)
      薄田健史, 青木重樹, 孫雨晨, 早川芳弘
    • Organizer
      第30回日本免疫毒性学会学術年会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Glycolysis in CD8+ T cells plays a major role in the onset of HLA-mediated idiosyncratic drug toxicity2023

    • Author(s)
      Takeshi Susukida, Shigeki Aoki, Yoshihiro Hayakawa
    • Organizer
      2023 International Joint Meeting of the 23rd International Conference on Cytochrome P450 and the 38th Annual Meeting of the Japanese Society for the Study of Xenobiotic
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Glycolysis in CD8+ T cells plays a major role in the onset of HLA-mediated idiosyncratic drug-induced autoimmune toxicity mouse model2023

    • Author(s)
      Takeshi Susukida, Shigeki Aoki, Yuchen Sun, Yoshihiro Hayakawa
    • Organizer
      第52回日本免疫学会学術集会
    • Related Report
      2023 Annual Research Report
  • [Presentation] 細胞内エネルギー代謝環境の変化がHLA多型の関与する薬物過敏症の発症に及ぼす影響2023

    • Author(s)
      薄田健史,青木重樹,早川芳弘
    • Organizer
      日本薬学会第143年会
    • Related Report
      2022 Research-status Report
  • [Presentation] 薬物-HLA相互作用による腫瘍免疫原性の改善を志向とした新規がん免疫治療戦略の開発2022

    • Author(s)
      薄田健史, 佐々木宗一郎,白柳智弘,青木重樹,伊藤晃成,早川芳弘
    • Organizer
      第26回日本がん免疫学会学術総会
    • Related Report
      2022 Research-status Report
  • [Presentation] 細胞内代謝環境の変化がHLA多型の関与する薬物過敏症の発症に及ぼす影響2022

    • Author(s)
      薄田健史,青木重樹,早川芳弘
    • Organizer
      第29回日本免疫毒性学会学術年会
    • Related Report
      2022 Research-status Report
  • [Presentation] Development of a novel anti-cancer immunotherapy based on tumor immunogenicity improvement by HLA-drug interaction2022

    • Author(s)
      Takeshi Susukida, So-ichiro Sasaki, Shigeki Aoki, Yoshihiro Hayakawa
    • Organizer
      第81回日本癌学会学術総会
    • Related Report
      2022 Research-status Report
  • [Presentation] Intracellular metabolism change affects the susceptibility to HLA-mediated idiosyncratic drug toxicity2022

    • Author(s)
      Takeshi Susukida, Shigeki Aoki, Yoshihiro Hayakawa
    • Organizer
      日本薬物動態学会第37回年会
    • Related Report
      2022 Research-status Report
  • [Presentation] キメラ型HLA導入マウスを用いた特異体質薬物毒性の評価2021

    • Author(s)
      風岡顯良, 薄田健史,桑原佐季,青木重樹,伊藤晃成
    • Organizer
      第28回 HAB研究機構学術年会
    • Related Report
      2021 Research-status Report
  • [Presentation] HLA-B*57:01 遺伝子導入マウスを用いた免疫抑制因子の排除によるアバカビル依存的特異体質毒性の再現2021

    • Author(s)
      青木重樹,桑原佐季,薄田健史,風岡顯良,伊藤晃成
    • Organizer
      日本薬物動態学会 第36回年会
    • Related Report
      2021 Research-status Report
  • [Remarks] 免疫の抑制系が医薬品による副作用発症をコントロールすることを発見

    • URL

      https://www.chiba-u.ac.jp/others/topics/info/post_1011.html

    • Related Report
      2021 Research-status Report
  • [Remarks] 免疫の抑制系が医薬品による副作用発症をコントロールすることを発見

    • URL

      https://www.u-toyama.ac.jp/news-education/35334/

    • Related Report
      2021 Research-status Report

URL: 

Published: 2021-04-28   Modified: 2025-01-30  

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