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Establishment of world-premier pachymeningitis animal model and development of new therapeutic option targeting TGF-beta.

Research Project

Project/Area Number 17K19663
Research Category

Grant-in-Aid for Challenging Research (Exploratory)

Allocation TypeMulti-year Fund
Research Field General internal medicine and related fields
Research InstitutionKyushu University

Principal Investigator

Kira Jun-ichi  九州大学, 医学研究院, 教授 (40183305)

Co-Investigator(Kenkyū-buntansha) 山崎 亮  九州大学, 医学研究院, 准教授 (10467946)
渡邉 充  九州大学, 医学研究院, 助教 (30748009)
篠田 紘司  九州大学, 医学研究院, 助教 (70747998)
Project Period (FY) 2017-06-30 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2018: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Fiscal Year 2017: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Keywords肥厚性硬膜炎 / 動物モデル / イルベサルタン / TGFbeta
Outline of Final Research Achievements

IgG4-related disease is a major cause of hypertrophic pachymeningitis (HP). HP lacks an animal model. We longitudinally evaluated dura in mice with a mutation (Y136F) in the linker for activation of T cells (LAT), which induced Th2 cell proliferation and IgG1 (IgG4 human equivalent) overexpression. Mice were administered daily oral irbesartan. Human IgG4-related, ANCA-related, and idiopathic HP dura were also examined. LATY136F mice had massive infiltration of B cells, IgG1+ cells, plasma cells, T cells, macrophages, and neutrophils in the dura, followed by marked fibrotic thickening. In dural lesions, TGF-β1 was produced in B cells and macrophages while TGF‐β receptor I (TGF-β RI) was upregulated on fibroblasts. A similar upregulation of TGF-β RI and pSMAD2/3 was present in autopsied dura of all three types of human HP. Irbesartan abolished dural inflammation and fibrotic thickening in treated LATY136F mice. TGF-β/SMAD pathway is a potential novel therapeutic target for HP.

Academic Significance and Societal Importance of the Research Achievements

肥厚性硬膜炎の根本的原因は不明であり、これまで動物モデルの報告も無く病態機序の検討や新規治療法開発といった基礎研究は全く進められていなかった。今回、私たちはLATY136Fマウスが世界初の肥厚性硬膜炎動物モデルとなることを報告し、さらにTGF-β/SMADシグナルが硬膜炎や線維性肥厚に対する治療標的となることをはじめて証明した。肥厚性硬膜炎の基礎研究を推進し、新規バイオマーカー探索や治療法開発を見据えた本研究の学術的・社会的意義は充分に高いと考えられる。

Report

(3 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • Research Products

    (14 results)

All 2019 2018 2017

All Journal Article (12 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 12 results,  Open Access: 8 results) Presentation (2 results)

  • [Journal Article] A novel model for treatment of hypertrophic pachymeningitis.2019

    • Author(s)
      Cui YW, et al.
    • Journal Title

      Ann Clin Transl Neurol.

      Volume: 6 Issue: 3 Pages: 431-444

    • DOI

      10.1002/acn3.715

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cerebrospinal fluid cytokine/chemokine/growth factor profiles in idiopathic hypertrophic pachymeningitis.2019

    • Author(s)
      Zhang X, et al
    • Journal Title

      J Neuroimmunol.

      Volume: 330 Pages: 38-43

    • DOI

      10.1016/j.jneuroim.2019.01.010

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Downregulation of Neuronal and Dendritic Connexin36-Made Electrical Synapses Without Glutamatergic Axon Terminals in Spinal Anterior Horn Cells From the Early Stage of Amyotrophic Lateral Sclerosis2018

    • Author(s)
      Kobayakawa Yuko、Masaki Katsuhisa、Yamasaki Ryo、Shiraishi Wataru、Hayashida Shotaro、Hayashi Shintaro、Okamoto Koichi、Matsushita Takuya、Kira Jun-ichi
    • Journal Title

      Frontiers in Neuroscience

      Volume: 12 Pages: 894-894

    • DOI

      10.3389/fnins.2018.00894

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Connexin 30 Deficiency Attenuates Chronic but Not Acute Phases of Experimental Autoimmune Encephalomyelitis Through Induction of Neuroprotective Microglia2018

    • Author(s)
      Fang Mei、Yamasaki Ryo、Li Guangrui、Masaki Katsuhisa、Yamaguchi Hiroo、Fujita Atsushi、Isobe Noriko、Kira Jun-ichi
    • Journal Title

      Frontiers in Immunology

      Volume: 9 Pages: 2588-2588

    • DOI

      10.3389/fimmu.2018.02588

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A comparison of brain magnetic resonance imaging lesions in multiple sclerosis by race with reference to disability progression.2018

    • Author(s)
      Nakamura Y, et al.
    • Journal Title

      J Neuroinflammation.

      Volume: 15 Issue: 1 Pages: 255-255

    • DOI

      10.1186/s12974-018-1295-1

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Connexin 30 deficiency attenuates A2 astrocyte responses and induces severe neurodegeneration in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride Parkinson’s disease animal model.2018

    • Author(s)
      Fujita A, Yamaguchi H, Yamasaki R, Cui Y, Matsuoka Y, Yamada KI, Kira JI.
    • Journal Title

      J Neuroinflammation.

      Volume: 15 Issue: 1 Pages: 227-227

    • DOI

      10.1186/s12974-018-1251-0

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A Novel Autoantibody against Plexin D1 in Patients with Neuropathic Pain.2018

    • Author(s)
      Fujii T, Yamasaki R, Iinuma K, Tsuchimoto D, Hayashi Y, Saitoh BY, Matsushita T, Kido MA, Aishima S, Nakanishi H, Nakabeppu Y, Kira JI.
    • Journal Title

      Annals of Neurology

      Volume: 84 Issue: 2 Pages: 208-224

    • DOI

      10.1002/ana.25279

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Oral phase dysphagia in facial onset sensory and motor neuronopathy.2018

    • Author(s)
      Watanabe M, et al.
    • Journal Title

      Brain Behav.

      Volume: 8 Issue: 6

    • DOI

      10.1002/brb3.999

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Association of Decreased Percentage of Vδ2+Vγ9+ γδ T Cells With Disease Severity in Multiple Sclerosis2018

    • Author(s)
      Maimaitijiang G, Shinoda K, Nakamura Y, Masaki K, Matsushita T, Isobe N, Yamasaki R, Yoshikai Y, Kira J.
    • Journal Title

      Frontiers in Immunology

      Volume: 9 Pages: 1-10

    • DOI

      10.3389/fimmu.2018.00748

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Novel disease-modifying anti-rheumatic drug iguratimod suppresses chronic experimental autoimmune encephalomyelitis by down-regulating activation of macrophages/microglia through an NF-κB pathway2018

    • Author(s)
      Guangrui Li, Ryo Yamasaki, Mei Fang, Katsuhisa Masaki, Hirofumi Ochi, Takuya Matsushita, Jun-ichi Kira
    • Journal Title

      SCIENTIFIC REPORTS

      Volume: 8 Issue: 1 Pages: 1933-1933

    • DOI

      10.1038/s41598-018-20390-5

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Parallel fluctuation of anti-neurofascin 155 antibody levels with clinico-electrophysiological findings in patients with chronic inflammatory demyelinating polyradiculoneuropathy2018

    • Author(s)
      Fujita Atsushi、Ogata Hidenori、Yamasaki Ryo、Matsushita Takuya、Kira Jun-ichi
    • Journal Title

      Journal of the Neurological Sciences

      Volume: 384 Pages: 107-112

    • DOI

      10.1016/j.jns.2017.11.035

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] HLA-DRB1*04:05 allele is associated with intracortical lesions on three-dimensional double inversion recovery images in Japanese patients with multiple sclerosis2017

    • Author(s)
      Shinoda Koji、Matsushita Takuya、Nakamura Yuri、Masaki Katsuhisa、Yamasaki Ryo、Yamaguchi Hiroo、Togao Osamu、Hiwatashi Akio、Kira Jun-ichi
    • Journal Title

      Multiple Sclerosis Journal

      Volume: 印刷中 Issue: 6 Pages: 710-720

    • DOI

      10.1177/1352458517707067

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Presentation] 世界初の肥厚性硬膜炎モデルを用いた創薬2018

    • Author(s)
      眞﨑勝久
    • Organizer
      第59回日本神経学会学術大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 世界初の肥厚性硬膜炎動物モデル作成とTGF-βシグナルを標的とした新規治療法開発2017

    • Author(s)
      崔訳文、眞﨑勝久、山﨑亮、林田翔太郎、山口浩雄、兵藤文紀、江藤比奈子、米川智、松下拓也、吉田眞理、Malie Malissen 、Bernard Malissen 、吉良潤一
    • Organizer
      第29回日本神経免疫学会学術集会
    • Related Report
      2017 Research-status Report

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Published: 2017-07-21   Modified: 2020-03-30  

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