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A novel immunotherapy of autoimmune disease by agonistic toll-like receptor 4 antibody

Research Project

Project/Area Number 26460058
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Biological pharmacy
Research InstitutionTohoku University

Principal Investigator

TSUKAMOTO HIROKI  東北大学, 薬学研究科, 助教 (70423605)

Co-Investigator(Renkei-kenkyūsha) TOMIOKA Yoshihisa  東北大学, 大学院薬学研究科, 教授 (00282062)
Project Period (FY) 2014-04-01 – 2017-03-31
Project Status Completed (Fiscal Year 2016)
Budget Amount *help
¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2014: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
KeywordsToll様受容体 / 自己免疫疾患 / 1型糖尿病 / 免疫寛容 / 機能性抗体 / 抗体医薬 / 自然免疫 / 骨髄由来免疫抑制細胞 / Toll-like receptor / モノクローナル抗体 / 1型糖尿病 / 制御性T細胞
Outline of Final Research Achievements

Type 1 diabetes (T1D) is currently an incurable disease as other most autoimmune diseases. The pathology of T1D progresses from a silent prodromal phase to a clinical phase in which insulin-producing pancreatic β cells is destructed by autoreactive T cells. In this study, we demonstrated that an agonistic monoclonal antibody (mAb) to Toll-like receptor 4 (TLR4) prevents from the onset of T1D by prophylactic treatment and also reverses the new-onset of T1D by therapeutic treatment in nonobese diabetic mice. An agonistic TLR4 mAb induces the tolerance in innate immunity via dendritic cells and myeloid-derived suppressor cells, which results in the suppression of autoimmune T cells. In addition, regulatory T cells are also induced by agonistic TLR4 mAb in both periphery and pancreatic islets. These results propose that a tolerance induction through innate immunity by TLR4 mAb may be a novel immunological approach to cure the autoimmune pathology in T1D.

Report

(4 results)
  • 2016 Annual Research Report   Final Research Report ( PDF )
  • 2015 Research-status Report
  • 2014 Research-status Report
  • Research Products

    (33 results)

All 2017 2016 2015 2014 Other

All Journal Article (13 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 11 results,  Open Access: 2 results,  Acknowledgement Compliant: 3 results) Presentation (18 results) (of which Int'l Joint Research: 1 results) Book (1 results) Remarks (1 results)

  • [Journal Article] Rapid and selective simultaneous quantitative analysis of modified nucleosides using multi-column liquid chromatography-tandem mass spectrometry.2017

    • Author(s)
      4.Jinno D, Kanemitsu Y, Saitoh K, Nankumo S, Tsukamoto H, Matsumoto Y, Abe T, Tomioka Y
    • Journal Title

      J Anal Sci Technol.

      Volume: 8 Issue: 1 Pages: 1-9

    • DOI

      10.1186/s40543-017-0110-4

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Anti-tumor immunity elicited by direct intratumoral administration of a recombinant adenovirus expressing either IL-28A/IFN-λ2 or IL-29/IFN-λ1.2016

    • Author(s)
      Hasegawa K, Tagawa M, Takagi K, Tsukamoto H, Tomioka Y, Suzuki T, Nishioka Y, Ohrui T, Numasaki M.
    • Journal Title

      Cancer Gene Ther

      Volume: 23(8) Issue: 8 Pages: 266-277

    • DOI

      10.1038/cgt.2016.29

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A Heterodimeric Cytokine, Consisting of IL-17A and IL-17F, Promotes Migration and Capillary-Like Tube Formation of Human Vascular Endothelial Cells2016

    • Author(s)
      Numasaki M, Tsukamoto H, Tomioka Y, Nishioka Y, Ohrui T.
    • Journal Title

      The Tohoku Journal of Experimental Medicine

      Volume: 240 Issue: 1 Pages: 47-56

    • DOI

      10.1620/tjem.240.47

    • NAID

      130005261734

    • ISSN
      0040-8727, 1349-3329
    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] TEX101, a glycoprotein essential for sperm fertility, is required for stable expression of Ly6k on testicular germ cells2016

    • Author(s)
      Endo S, Yoshitake H, Tsukamoto H, Matsuura H, Kato K, Sakuraba M, Takamori K, Fujiwara H, Takeda S, Araki Y
    • Journal Title

      Sci Rep

      Volume: 6 Issue: 1 Pages: 23616-23616

    • DOI

      10.1038/srep23616

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] イナビル添加乳糖に夾雑する乳タンパク質によってアナフィラキシーを呈した1例2016

    • Author(s)
      森川みき、金光祥臣、塚本宏樹、富岡佳久
    • Journal Title

      アレルギー

      Volume: 65(3)

    • Related Report
      2015 Research-status Report
    • Peer Reviewed
  • [Journal Article] Toll様受容体4抑制抗体の作用機序とそのエピトープ2016

    • Author(s)
      塚本宏樹
    • Journal Title

      細胞

      Volume: 48(4) Pages: 50-52

    • Related Report
      2015 Research-status Report
  • [Journal Article] Reversal of New-Onset Type 1 Diabetes With an Agonistic TLR4/MD-2 Monoclonal Antibody2015

    • Author(s)
      Bednar, K.J., Tsukamoto, H., Kachapati, K., Ohta, S., Wu, Y., Katz, J.D., Ascherman, D.P. & Ridgway, W.M.
    • Journal Title

      Diabetes

      Volume: 64 Issue: 10 Pages: 3614-3626

    • DOI

      10.2337/db14-1868

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Multi-inhibitory effects of A2A adenosine receptor signaling on neutrophil adhesion under flow2015

    • Author(s)
      Yago T, Tsukamoto H, Liu Z, Wang Y, Thompson LF, McEver RP
    • Journal Title

      J Immunol

      Volume: 195(8) Issue: 8 Pages: 3880-3889

    • DOI

      10.4049/jimmunol.1500775

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Leucine-rich repeat 2 of human Toll-like receptor 4 contains the binding site for inhibitory monoclonal antibodies2015

    • Author(s)
      Tsukamoto H, Ukai I, Yamagata Y, Takeuchi S, Kubota K, Kozakai S, Suzuki N, Kimoto M, Tomioka Y
    • Journal Title

      FEBS Lett

      Volume: 589(24 Pt B) Issue: 24PartB Pages: 3893-3898

    • DOI

      10.1016/j.febslet.2015.11.018

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] 【研究戦略・YAKU学~研究現場から~】 機能性抗体によるToll様受容体の活性制御を基盤とした敗血症治療薬開発2015

    • Author(s)
      塚本宏樹
    • Journal Title

      薬事日報

      Volume: 11542 Pages: 8-8

    • Related Report
      2014 Research-status Report
  • [Journal Article] Extracellular Adenosine Is a Therapeutic Target for Limiting Graft-<i>versus</i>-Host Disease and Enhancing the Graft-<i>versus</i>-Tumor Effect against Hematopoietic Malignancy2014

    • Author(s)
      Tsukamoto H
    • Journal Title

      YAKUGAKU ZASSHI

      Volume: 134 Issue: 10 Pages: 1021-1027

    • DOI

      10.1248/yakushi.14-00184

    • NAID

      130004693882

    • ISSN
      0031-6903, 1347-5231
    • Year and Date
      2014-10-01
    • Related Report
      2014 Research-status Report
    • Peer Reviewed
  • [Journal Article] Immune regulation via the generation of extracellular adenosine by CD732014

    • Author(s)
      Tsukamoto H
    • Journal Title

      Seikagaku

      Volume: 86 Pages: 766-769

    • NAID

      40020314143

    • Related Report
      2014 Research-status Report
    • Peer Reviewed
  • [Journal Article] A validated quantitative liquid chromatography-tandem quadrupole mass spectrometry method for monitoring isotopologues to evaluate global modified cytosine ratios in genomic DNA2014

    • Author(s)
      Tsuji M, Matsunaga H, Jinno D, Tsukamoto H, Suzuki N, Tomioka Y
    • Journal Title

      J Chromatogr B Analyt Technol Biomed Life Sci

      Volume: 953-954 Pages: 38-47

    • DOI

      10.1016/j.jchromb.2014.01.050

    • Related Report
      2014 Research-status Report
    • Peer Reviewed
  • [Presentation] サイクリックADP リボース安定同位体の合成2017

    • Author(s)
      齋藤一樹、田中晃佑、鈴木千登世、阿部高明、金光祥臣、塚本宏樹、松本洋太郎、富岡佳久
    • Organizer
      日本薬学会第137年会
    • Place of Presentation
      仙台市(仙台国際センター・東北大学)
    • Year and Date
      2017-03-25
    • Related Report
      2016 Annual Research Report
  • [Presentation] 異なるシグナル誘導活性を持つToll様受容体4刺激抗体による抗原特異的抗体産生抑制効果2017

    • Author(s)
      小林洋平、小坂井沙緖、久保田佳苗、武内偲乃、金光祥臣、松本洋太郎、塚本宏樹、富岡佳久
    • Organizer
      日本薬学会第137年会
    • Place of Presentation
      仙台市(仙台国際センター・東北大学)
    • Year and Date
      2017-03-25
    • Related Report
      2016 Annual Research Report
  • [Presentation] ヒトToll様受容体4活性化に必要なleucine-rich repeat 13は抑制抗体によって認識される2017

    • Author(s)
      山形由貴、大久保美咲、鵜飼一歩、金光祥臣、松本洋太郎、塚本宏樹、富岡佳久
    • Organizer
      日本薬学会第137年会
    • Place of Presentation
      仙台市(仙台国際センター・東北大学)
    • Year and Date
      2017-03-25
    • Related Report
      2016 Annual Research Report
  • [Presentation] LC-MSを用いた細胞内サイクリックADPリボース高感度定量法の構築2017

    • Author(s)
      齋藤一樹、金光祥臣、田中晃佑、鈴木千登世、阿部高明、塚本宏樹、松本洋太郎、富岡佳久
    • Organizer
      日本薬学会第137年会
    • Place of Presentation
      仙台市(仙台国際センター・東北大学)
    • Year and Date
      2017-03-25
    • Related Report
      2016 Annual Research Report
  • [Presentation] 不活性型二量体構造の誘導を介した抑制型ヒトToll様受容体4抗体の新規作用機序2017

    • Author(s)
      山形由貴、鵜飼一歩、金光祥臣、小林洋平、松本洋太郎、塚本宏樹、富岡佳久
    • Organizer
      日本薬学会第137年会
    • Place of Presentation
      仙台市(仙台国際センター・東北大学)
    • Year and Date
      2017-03-25
    • Related Report
      2016 Annual Research Report
  • [Presentation] LPS-binding proteinはToll様受容体4の二量体化・内在化を介してTRIF依存的IKKε/TBK1/IRF3経路を活性化する2017

    • Author(s)
      久保田佳苗、武内偲乃、鵜飼一歩、小坂井沙緒、金光祥臣、松本洋太郎、塚本宏樹、富岡佳久
    • Organizer
      日本薬学会第137年会
    • Place of Presentation
      仙台市(仙台国際センター・東北大学)
    • Year and Date
      2017-03-25
    • Related Report
      2016 Annual Research Report
  • [Presentation] Toll様受容体4シグナルによるGr1+CD11b+細胞誘導を介した抗原特異的抗体産生抑制機序2017

    • Author(s)
      小坂井沙緒、小林洋平、金光祥臣、松本洋太郎、塚本宏樹、富岡佳久
    • Organizer
      日本薬学会第137年会
    • Place of Presentation
      仙台市(仙台国際センター・東北大学)
    • Year and Date
      2017-03-25
    • Related Report
      2016 Annual Research Report
  • [Presentation] LC-MSを用いた高感度サイクリックADPリボース定量法の構築2016

    • Author(s)
      齋藤一樹、金光祥臣、松本洋太郎、塚本宏樹、鈴木千登世、阿部高明、富岡佳久
    • Organizer
      第55回日本薬学会東北支部大会
    • Place of Presentation
      郡山市(奥羽大学)
    • Year and Date
      2016-09-25
    • Related Report
      2016 Annual Research Report
  • [Presentation] LPS-binding proteinはリポ多糖によるToll様受容体4の内在化を誘導する2016

    • Author(s)
      武内偲乃、久保田佳苗、小坂井沙緒、塚本宏樹、富岡佳久
    • Organizer
      第55回日本薬学会東北支部大会
    • Place of Presentation
      郡山市(奥羽大学)
    • Year and Date
      2016-09-25
    • Related Report
      2016 Annual Research Report
  • [Presentation] イナビルによるアナフィラキシー症例報告と添加乳糖に夾雑するアレルゲン乳タンパク質の同定2016

    • Author(s)
      金光祥臣、森川みき、塚本宏樹、松本洋太郎、森川昭正、富岡佳久
    • Organizer
      第26回日本医療薬学会年会
    • Place of Presentation
      京都市(国立京都国際会館・グランドプリンスホテル京都)
    • Year and Date
      2016-09-17
    • Related Report
      2016 Annual Research Report
  • [Presentation] Simultaneous quantitative analysis of modified nucleosides by liquid chromatography-tandem mass spectrometry2015

    • Author(s)
      Jinno D, Saitoh K, Nankumo S, Kanemitsu Y, Tsukamoto H, Matsumoto Y, Mishima E, Suzuki C, Abe T, Tomioka Y
    • Organizer
      Pharmaceutical Science Symposium 2015 in Sendai
    • Place of Presentation
      仙台(東北大学片平キャンパス))
    • Year and Date
      2015-11-16
    • Related Report
      2015 Research-status Report
    • Int'l Joint Research
  • [Presentation] LC/MS/MSによる修飾核酸一斉定量法の構築と応用2015

    • Author(s)
      陣野大輔、齋藤一樹、南雲信之介、金光祥臣、塚本宏樹、松本洋太郎、三島英換、鈴木千登世、阿部高明、富岡佳久
    • Organizer
      第54回日本薬学会東北支部大会
    • Place of Presentation
      岩手(岩手医科大学矢巾キャンパス)
    • Year and Date
      2015-09-26
    • Related Report
      2015 Research-status Report
  • [Presentation] 新規ヒトTLR4モノクローナル抑制抗体のエピトープ解析2015

    • Author(s)
      鵜飼一歩、塚本宏樹、山形由貴、鈴木直人、富岡佳久
    • Organizer
      日本薬学会第135年会
    • Place of Presentation
      神戸
    • Year and Date
      2015-03-26 – 2015-03-28
    • Related Report
      2014 Research-status Report
  • [Presentation] CD14のLPS結合能とTLR4内在化の機能連関2015

    • Author(s)
      武内偲乃、塚本宏樹、鵜飼一歩、山形由貴、久保田佳苗、小坂井沙緒、富岡佳久
    • Organizer
      日本薬学会第135年会
    • Place of Presentation
      神戸
    • Year and Date
      2015-03-26 – 2015-03-28
    • Related Report
      2014 Research-status Report
  • [Presentation] 機能性Toll様受容体4抗体による敗血症治療と病態解析への応用(シンポジスト)2014

    • Author(s)
      塚本宏樹、富岡佳久
    • Organizer
      第16回応用薬理シンポジウム
    • Place of Presentation
      松島
    • Year and Date
      2014-12-04 – 2014-12-05
    • Related Report
      2014 Research-status Report
  • [Presentation] 機能抑制型抗ヒトTLR4モノクローナル抗体は不活性型TLR4二量体構造を誘導する2014

    • Author(s)
      山形由貴、塚本宏樹、鵜飼一歩、鈴木直人、富岡佳久
    • Organizer
      第87回日本生化学会大会
    • Place of Presentation
      京都
    • Year and Date
      2014-10-15 – 2014-10-18
    • Related Report
      2014 Research-status Report
  • [Presentation] シースレスインターフェイスを用いたCE-MSによる低分子化合物分析法の検討2014

    • Author(s)
      陣野大輔、齋藤一樹、由利謙典、武川力永、塚本宏樹、鈴木直人、阿部高明、富岡佳久
    • Organizer
      第53回日本薬学会東北支部大会
    • Place of Presentation
      いわき
    • Year and Date
      2014-10-05
    • Related Report
      2014 Research-status Report
  • [Presentation] A validated quantitative LC-MS/MS method using isotopic MRM transitions to evaluate global ratios of modified cytosines2014

    • Author(s)
      Tsuji M, Matsunaga H, Jinno D, Tsukamoto H, Suzuki N, Tomioka Y
    • Organizer
      20th International Mass Spectrometry Conference (IMSC 2014)
    • Place of Presentation
      Geneva, Switzerland
    • Year and Date
      2014-08-24 – 2014-08-29
    • Related Report
      2014 Research-status Report
  • [Book] Bioactive Lipid Mediators-Current Reviews and Protocols2015

    • Author(s)
      Takahashi T, Saigusa D, Takeda C, Saito K, Suzuki N, Tsukamoto H, Tomioka Y
    • Total Pages
      426
    • Publisher
      Springer Japan
    • Related Report
      2015 Research-status Report
  • [Remarks] 東北大学大学院薬学研究科がん化学療法薬学分野ホームページ

    • URL

      http://www.pharm.tohoku.ac.jp/~gankagak/Gann_Top.html

    • Related Report
      2016 Annual Research Report 2015 Research-status Report

URL: 

Published: 2014-04-04   Modified: 2018-03-22  

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