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Exploration of therapeutic targets which are involved in the pathogenesis of Sjogren's syndrome aiming at ion channels.

Research Project

Project/Area Number 16K09905
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Collagenous pathology/Allergology
Research InstitutionKeio University

Principal Investigator

Yoshimoto Keiko  慶應義塾大学, 医学部(信濃町), 研究員 (20383292)

Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywordsシェーグレン症候群 / BAFF / BAFF受容体 / イオンチャンネル / シェーグレン症候群n / 単球 / B細胞 / 自己抗体 / IL-6 / IgG / 膠原病学
Outline of Final Research Achievements

BAFF and its receptor (BR3) are involved in the pathogenesis of Sjogren’s syndrome (SS). We demonstrated that the expression levels of BR3 and a voltage-gated sodium channel in SS monocytes were significantly higher than those of healthy controls and that elevation was correlated with serum IgG level of the patients. In addition, we have successfully discovered a low molecular weight compound which has inhibitory activities against both BAFF signaling pathways and a sodium channel. In this study, we tested the effects of this compound on production of autoantibodies and inflammatory cytokines by using autoimmune model mice. As a results, we found that this compound inhibited production of anti-dsDNA antibody and inflammatory cytokines, such as IL-6 and IL-10. Moreover, this compound also suppressed infiltration of B cells into the organs, such as lachrymal glands and kidney. Notably, we have found a novel compound which is expected more efficacy on the suppression of B cell function.

Academic Significance and Societal Importance of the Research Achievements

本研究は免疫難病であるシェーグレン症候群(SS)の患者単球の異常活性化機構と病態への関与を明らかにするものである。具体的には患者末梢血単球で発現が亢進しているイオンチャンネル同定し、これを介したシグナルとBAFFシグナルの関与を明らかにした。さらに研究代表者らはこの機構を阻害する作用を有する独自の化合物を得て、SSモデル動物での薬効薬理試験を実施し、有効性を検証することに成功した。本研究はSSの発症メカニズムを明らかにするという点で学術的に有意義であるばかりでなく、きわめて独創性の高い治療標的を見出すことにつながり、SSの新規な治療法の開発という点においても有用である。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (35 results)

All 2018 2017 2016

All Journal Article (12 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 11 results,  Open Access: 7 results,  Acknowledgement Compliant: 5 results) Presentation (22 results) (of which Int'l Joint Research: 13 results,  Invited: 2 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] Restoration of Decreased T Helper 1 and CD8+ T Cell Subsets Is Associated With Regression of Lymphoproliferative Disorders Developed During Methotrexate Treatment2018

    • Author(s)
      Saito Shuntaro、Suzuki Katsuya、Yoshimoto Keiko、Kaneko Yuko、Yamaoka Kunihiro、Shimizu Takayuki、Mori Takehiko、Okamoto Shinichiro、Kameyama Kaori、Amano Koichi、Tamaru Jun-ichi、Tokuhira Michihide、Takeuchi Tsutomu
    • Journal Title

      Frontiers in Immunology

      Volume: 9 Pages: 621-621

    • DOI

      10.3389/fimmu.2018.00621

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Multi-omics monitoring of drug response in rheumatoid arthritis in pursuit of molecular remission.2018

    • Author(s)
      Tasaki S, Suzuki K, Kassai Y, Takeshita M, Murota A, Kondo Y, Ando T, Nakayama Y, Okuzono Y, Takiguchi M, Kurisu R, Miyazaki T, Yoshimoto K, Yasuoka H, Yamaoka K, Morita R, Yoshimura A, Toyoshiba H, Takeuchi T.
    • Journal Title

      Nat Commun

      Volume: 9(1) Issue: 1 Pages: 2755-2755

    • DOI

      10.1038/s41467-018-05044-4

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 2)Interleukin-4 contributes to the shift of balance of IgG subclasses toward IgG4 in IgG4-related disease.2018

    • Author(s)
      Akiyama M, Yasuoka H, Yoshimoto K, Takeuchi T.
    • Journal Title

      Cytokine

      Volume: 110 Pages: 416-419

    • DOI

      10.1016/j.cyto.2018.05.009

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Increased proportion of a CD38highIgD+ B cell subset in peripheral blood is associated with clinical and immunological features in patients with primary Sjögren's syndrome.2018

    • Author(s)
      Ishioka-Takei E, Yoshimoto K, Suzuki K, Nishikawa A, Yasuoka H, Yamaoka K, Takeuti T.
    • Journal Title

      Clinical Immnunology

      Volume: 187 Pages: 85-91

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] シェーグレン症候群の病態におけるBAFF/BAFF受容体の役割と治療への展開2017

    • Author(s)
      吉本桂子 竹内 勤
    • Journal Title

      臨床免疫・アレルギー科

      Volume: 67 Pages: 377-382

    • Related Report
      2017 Research-status Report
  • [Journal Article] CC-chemokine ligand 18 is a useful biomarker associated with disease activity in IgG4-related disease.2017

    • Author(s)
      Akiyama M, Yasuoka H, Yoshimoto K, Takeuchi T.
    • Journal Title

      Ann Rheum Dis

      Volume: - Issue: 9 Pages: 1386-1387

    • DOI

      10.1136/annrheumdis-2017-212110

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Multiomic disease signatures converge to cytotoxic CD8 T cells in primary Sjögren's syndrome.2017

    • Author(s)
      Tasaki S1,2, Suzuki K3, Nishikawa A3, Kassai Y4, Takiguchi M4, Kurisu R4, Okuzono Y4, Miyazaki T4,5, Takeshita M3, Yoshimoto K3, Yasuoka H3, Yamaoka K3, Ikeura K6, Tsunoda K6, Morita R7, Yoshimura A7, Toyoshiba H1, Takeuchi T3.
    • Journal Title

      Ann Rheum Dis

      Volume: 76 Issue: 8 Pages: 1458-1466

    • DOI

      10.1136/annrheumdis-2016-210788

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] CD14brightCD16+ intermedicate monocytes are induced by interleukin-10 and positively correlated with disease activity in rheumatoid arthritis.2017

    • Author(s)
      Tsukamoto M, Seta N, Yoshimoto K, Suzuki K, Yamaoka K, Takeuchi T
    • Journal Title

      Arthritis Res Ther

      Volume: 19 Issue: 1 Pages: 28-28

    • DOI

      10.1186/s13075-016-1216-6

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Identification of definitive serum biomarkers associated with disease activity in primary Sjogren's syndrome.2016

    • Author(s)
      Nishikawa A, Suzuki K, Kassai Y, Gotou Y, Takiguchi M, Miyazaki T, Yoshimoto K, Yasuoka H, Yamaoka K, Morita R, Yoshimura A, Takeuchi T.
    • Journal Title

      Arthritis Res Ther.

      Volume: 18 Issue: 1 Pages: 106-106

    • DOI

      10.1186/s13075-016-1006-1

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Bendamustine increases interleukin-10 secretion from B cells via p38 MAP kinase activation.2016

    • Author(s)
      Lu L, Yoshimoto K, Morita A, Kameda H, Takeuchi T
    • Journal Title

      Int Immunopharmacol.

      Volume: 39 Pages: 273-279

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Early Prognostic Factors Associated with the Efficacy of Infliximab Treatment for Patients with Rheumatoid Arthritis with Inadequate Response to Methotrexate.2016

    • Author(s)
      Hayashi S, Suzuki K, Yoshimoto K, Takeshita M, Kurasawa T, Yamaoka K, Takeuchi T
    • Journal Title

      Rheumatol Ther.

      Volume: 3 Pages: 155-166

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Fcg receptor 3B polymorphism is associated with hypersensitivity reactions to adalimumab in Japanese patients with rheumatoid arthritis.2016

    • Author(s)
      Tsukamoto M, Kameda H, Ohshige T, Kaneko Y, Yoshimoto K, Suzuki K, Takeuchi T
    • Journal Title

      Mod Rheumatol.

      Volume: 18 Pages: 1-4

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Presentation] A Low molecular weight BAFF receptor antagonist inhibits differentiation of human peripheral B cells into plasma blasts/plasma cells in vitro.2018

    • Author(s)
      Keiko Yoshimoto, Noriyasu Seki, Katsuya Suzuki, Kunio Sugahara, Tsutomu Takeuchi
    • Organizer
      IMMUNOLOGY 2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] A low molecular weight BAFF signaling inhibitor, BIK-13, ameliorates B cell activation in vitro and in vivo autoimmune models and consequently suppresses production of IgG and cytokines2018

    • Author(s)
      Keiko Yoshimoto, Noriyasu Seki, Katsuya Suzuki, Kunio Sugahara, Kenji Chiba, Tsutomu Takeuchi
    • Organizer
      EULAR 2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Possible involvement of BAFF and matrixmetalloproteinase-9 in the activation of monocytes of patients with primary Sjogren’s syndrome.2018

    • Author(s)
      Keiko Yoshimoto, Katsuya Suzuki, Tsutomu Takeuchi
    • Organizer
      EULAR 2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 原発性シェーグレン症候群患者末梢血単球の活性化におけるBAFFとMMP9の関与2018

    • Author(s)
      吉本桂子、鈴木勝也、竹内 勤
    • Organizer
      第39回日本炎症・再生医学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] BAFFシグナルを標的とした低分子化合物を用いたシェーグレン症候群治療薬創製への試み2018

    • Author(s)
      吉本桂子、鈴木勝也、関 則靖、菅原邦夫、千葉健治、竹内 勤
    • Organizer
      第27回日本シェーグレン症候群学会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] 原発性シェーグレン症候群患者末梢血単球活性化におけるBAFFとMMP-9の関与2018

    • Author(s)
      吉本桂子、鈴木勝也、竹内 勤
    • Organizer
      第27回日本シェーグレン症候群学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Localization of the voltage-gated sodium channel 1.7 in peripheral monocytes contributes to activation of BAFF signaling in monocytes of patients with primary Sjogren’s syndrome.2018

    • Author(s)
      Keiko Yoshimoto, Yumi Ikeda, Katsuya Suzuki, Tsutomu Takeuchi
    • Organizer
      ACR ARP 2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Reduced expression of CX3CR1 in peripheral CD14++CD16+ monocytes is a novel feature of patients with systemic lupus erythematosus.2018

    • Author(s)
      Keiko Yoshimoto, Katsuya Suzuki, Shuntaro Saito, Jun Kikuchi, Tsutomu Takeuchi
    • Organizer
      ACR ARP 2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] A low molecular weight BAFF signaling inhibitor reduces production of autoantibody and suppresses infiltration of B cells into the organs in autoimmune model mice.2018

    • Author(s)
      Keiko Yoshimoto, Katsuya Suzuki, Noriyasu Seki, Kunio Sugahara, Kenji Chiba, Tsutomu Takeuchi
    • Organizer
      第47回日本免疫学会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Inhibition of BAFF binding to its receptor, BR3, with low molecular weight compounds results in suppression of activation of monocytes and B cells in vitro and in vivo model of autoimmune diseases.2017

    • Author(s)
      Keiko Yoshimoto, Katsuya Suzuki, Kunio Sugahara, Tsutomu Takeuchi
    • Organizer
      1.Immunology 2017
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Low molecular weight BAFF signaling inhibitors ameliorate IL-6, IL-10 and IgG production in vitro and in vivo models of autoimmune diseases.2017

    • Author(s)
      Keiko Yoshimoto, Katsuya Suzuki, Kunio Sugahara, Tsutomu Takeuchi
    • Organizer
      EULAR 2017
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] BAFF-BAFF受容体結合阻害作用を有する低分子化合物は形質芽細胞および形質細胞分化を抑制する2017

    • Author(s)
      吉本桂子、関 則靖、鈴木勝也、菅原邦夫、竹内 勤
    • Organizer
      第26回日本シェーグレン症候群学会
    • Related Report
      2017 Research-status Report
  • [Presentation] B細胞活性化因子(BAFF)およびその受容体を標的とした自己免疫疾患治療薬創製の試み2017

    • Author(s)
      吉本桂子、鈴木勝也、関 則靖、菅原邦夫、千葉健治、竹内 勤
    • Organizer
      第45回日本臨床免疫学会
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] Increased expression of BAFF receptor on monocytes is a contributory factor of IgG overproduction in patients with primary Sjögren's syndrome.2017

    • Author(s)
      Keiko Yoshimoto, Katsuya Suzuki and Tsutomu Takeuchi
    • Organizer
      Cytokines 2017
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Low molecular weight BAFF receptor antagonists restrain infiltration of B cells into organs of autoimmune model mice by suppressing B cell activation.2017

    • Author(s)
      Keiko Yoshimoto, Noriyasu Seki, Katsuya Suzuki, Kunio Sugahara, Tsutomu Takeuchi
    • Organizer
      ACR Annual Meeting 2017
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] BAFF signaling inhibitors ameliorate enhanced production of IL-6 and IL-10 by pSS monocytes and consequently suppress IgG overproduction by affecting differentiation of B cells.2017

    • Author(s)
      Keiko Yoshimoto, Noriyasu Seki, Katsuya Suzuki, Kunio Sugahara Tsutomu Takeuchi
    • Organizer
      第46回日本免疫学会
    • Related Report
      2017 Research-status Report
  • [Presentation] Low molecular weight compound BAFF binding inhibitors suppress activation of monocytes through BAFF signaling involved in NF-kB pathways.2016

    • Author(s)
      Yoshimoto K, Suzuki K, Sugahara K, Takeuchi T
    • Organizer
      第45回日本免疫学会学術集会
    • Place of Presentation
      沖縄コンベンションセンター (沖縄県那覇市)
    • Year and Date
      2016-12-05
    • Related Report
      2016 Research-status Report
  • [Presentation] BAFF receptor antagonisits suppress differentiation of B cells in vitro and are frug candidates for primary Sjogren's syndrome.2016

    • Author(s)
      Yoshimoto K, Seki N, Suzuki K, Sugahara K, Takeuchi T
    • Organizer
      2016 ACR/ARHP Annual Meeting
    • Place of Presentation
      Washington DC convention center ワシントンDC(アメリカ)
    • Year and Date
      2016-11-11
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] Low molecular weight-BAFF receptor antagomists are drug candidates for primary Sjogren's syndrome.2016

    • Author(s)
      Yoshimoto K, Suzuki K, Sugahara K, Takeuchi T
    • Organizer
      Biomarkers and Targeted Therapeutics in Sjogren's
    • Place of Presentation
      Oklahoma City Convention Center オクラホマシティー(アメリカ)
    • Year and Date
      2016-09-19
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] Enhanced expression of BAFF receptor (BR3) on peripheral monocytes contributes production of IgG by B cells through IL-6 signaling in patients with primary Sjogren's syndrome.2016

    • Author(s)
      Yoshimoto K, Ishioka E, Nishikawa A, Suzuki K, Takeuchi T
    • Organizer
      International Congress of Immunology
    • Place of Presentation
      Melbourne COnvention Center メルボルン(オーストラリア)
    • Year and Date
      2016-08-21
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] Low molecular weight compounds which inhibit BAFF binding to its receptor, BR3, suppress activation of monocytes.2016

    • Author(s)
      Yoshimoto K, Ishioka E, Nishikawa A, Suzuki K, Ito T, Sugano T, Yamada H, Okuda A, Okuda H, Ishikawa H, Doi T, Hirokawa T, Takeuchi T
    • Organizer
      IMMUNOLOGY 2016
    • Place of Presentation
      Seattle Convention Center  シアトル(アメリカ)
    • Year and Date
      2016-05-13
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] シェーグレン症候群治療薬としてのBAFF-BAFF受容体(BR3)結合阻害剤の検討2016

    • Author(s)
      吉本桂子、石岡江梨子、西川あゆみ、鈴木勝也、菅原邦夫、竹内 勤
    • Organizer
      第60回日本リウマチ学会総会・学術集会
    • Place of Presentation
      パシフィコ横浜(神奈川県横浜市)
    • Year and Date
      2016-04-21
    • Related Report
      2016 Research-status Report
  • [Patent(Industrial Property Rights)] ピロロピリミジン化合物を有効成分とする炎症性疾患の予防及び/又は治療剤2018

    • Inventor(s)
      吉本桂子、鈴木勝也、竹内 勤
    • Industrial Property Rights Holder
      吉本桂子、鈴木勝也、竹内 勤
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2018-092068
    • Filing Date
      2018
    • Related Report
      2018 Annual Research Report

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Published: 2016-04-21   Modified: 2020-03-30  

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