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Development of rheumatoid arthritis-directed human immunology

Research Project

Project/Area Number 23229007
Research Category

Grant-in-Aid for Scientific Research (S)

Allocation TypeSingle-year Grants
Research Field 膠原病・アレルギー・感染症内科学
Research InstitutionThe University of Tokyo

Principal Investigator

YAMAMOTO KAZUHIKO  東京大学, 医学部附属病院, 教授 (80191394)

Co-Investigator(Kenkyū-buntansha) OKAMURA TOMOHISA  東京大学, 医学部附属病院, 特任助教 (10528996)
SHODA HIROFUMI  東京大学, 医学部附属病院, 助教 (20529036)
SUMITOMO SHUJI  東京大学, 医学部附属病院, 助教 (20392996)
SHIBUYA MIHOKO  東京大学, 医学部附属病院, 助教 (20366363)
IWASAKI YUKIKO  東京大学, 医学部附属病院, 助教 (30592935)
岡本 明子  東京大学, 学内共同利用施設等, 助教 (40431861)
Project Period (FY) 2011-04-01 – 2016-03-31
Project Status Completed (Fiscal Year 2015)
Budget Amount *help
¥214,760,000 (Direct Cost: ¥165,200,000、Indirect Cost: ¥49,560,000)
Fiscal Year 2015: ¥42,640,000 (Direct Cost: ¥32,800,000、Indirect Cost: ¥9,840,000)
Fiscal Year 2014: ¥42,640,000 (Direct Cost: ¥32,800,000、Indirect Cost: ¥9,840,000)
Fiscal Year 2013: ¥42,640,000 (Direct Cost: ¥32,800,000、Indirect Cost: ¥9,840,000)
Fiscal Year 2012: ¥42,640,000 (Direct Cost: ¥32,800,000、Indirect Cost: ¥9,840,000)
Fiscal Year 2011: ¥44,200,000 (Direct Cost: ¥34,000,000、Indirect Cost: ¥10,200,000)
Keywordsゲノム / 内科 / 免疫学 / 組織・細胞 / 生体分子 / 細胞・組織
Outline of Final Research Achievements

This project aimed to address the function of lymphocytes in rheumatoid arthritis(RA) with regard to (1) regulatory T cells (Treg), (2) gene polymorphisms, and (3) antigen-specific CD4+ T cells. (1) TGF-beta3 producing LAG3+Treg were identified in mice and the frequency of LAG3+Treg showed a significant decrease in active RA. (2) Transcriptome and genome wide polymorphism examinations in 100 healthy controls enabled us to establish a method predicting transcriptome from genetic polymorphisms. (3) Effector and regulatory T cells recognized different BiP epitopes and their balance showed a deviation toward BiP-specific effector T cells.

Assessment Rating
Verification Result (Rating)

A

Assessment Rating
Result (Rating)

A-: Progress in the research is steadily towards the initial goal. However, further efforts are necessary as a part of the research progress is delayed.

Report

(9 results)
  • 2016 Research Progress Assessment (Verification Result) ( PDF )
  • 2015 Annual Research Report   Final Research Report ( PDF )
  • 2014 Annual Research Report   Abstract(Research Progress Assessment) ( PDF )   Research Progress Assessment (Result) ( PDF )
  • 2013 Annual Research Report
  • 2012 Annual Research Report
  • 2011 Annual Research Report
  • Research Products

    (40 results)

All 2016 2015 2014 2013 2012 2011 Other

All Journal Article (23 results) (of which Peer Reviewed: 23 results,  Open Access: 7 results,  Acknowledgement Compliant: 4 results) Presentation (15 results) (of which Int'l Joint Research: 5 results,  Invited: 15 results) Remarks (1 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] 1.Immune responses to Mycobacterium heat shock protein 70 accompany self-reactivity to human BiP in rheumatoid arthritis2016

    • Author(s)
      Shoda H, Hanata N, Sumitomo S, Okamura T, Fujio K, Yamamoto K
    • Journal Title

      Scientific Reports

      Volume: 6 Issue: 1 Pages: 22486-22486

    • DOI

      10.1038/srep22486

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Therapeutic potential of regulatory cytokines that target B cells.2016

    • Author(s)
      Fujio Keishi, Okamura Tomohisa, Sumitomo Shuji, Yamamoto Kazuhiko
    • Journal Title

      Internal Immunology

      Volume: 28 Issue: 4 Pages: 189-195

    • DOI

      10.1093/intimm/dxv069

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Role of TGF-β3 in the regulation of immune responses2015

    • Author(s)
      Okamura T, Morita K, Iwasaki Y, Inoue M, Komai T, Fujio K, Yamamoto K
    • Journal Title

      Clin Exp Rheumatol

      Volume: 33

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Peptidylarginine deiminase type 4 deficiency reduced arthritis severity in a glucose-6-phosphate isomerase-induced arthritis model2015

    • Author(s)
      Seri Y, Shoda H, Suzuki A, Matsumoto I, Sumida T, Fujio K, Yamamoto K
    • Journal Title

      Sci Rep

      Volume: 5 Issue: 1 Pages: 13041-13041

    • DOI

      10.1038/srep13041

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Quantitative and qualitative characterization of expanded CD4 + T cell clones in rheumatoid arthritis patients2015

    • Author(s)
      Ishigaki K, Shoda H, Kochi Y, Yasui T, Kadono Y, Tanaka S, Fujio K, Yamamoto K
    • Journal Title

      Scientific Reports

      Volume: 5 Issue: 1 Pages: 12937-12937

    • DOI

      10.1038/srep12937

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] A new T-cell activation mode for suboptimal doses of antigen under the full activation of T cells with different specificity.2015

    • Author(s)
      Shibuya M, Fujio K, Shoda H, Okamura T, Okamoto A, Sumitomo S, Yamamoto K.
    • Journal Title

      Europian Journal of Immunology

      Volume: in press Issue: 6 Pages: 1643-53

    • DOI

      10.1002/eji.201444965

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed
  • [Journal Article] TGF-β3-expressing CD4+CD25(-)LAG3+ regulatory T cells control humoral immune responses2015

    • Author(s)
      Okamura T, Sumitomo S, Morita K, Iwasaki Y, Inoue M, Nakachi S, Komai T, Shoda H, Miyazaki J, Fujio K, Yamamoto K.
    • Journal Title

      Nature Communications

      Volume: 6 Issue: 1 Pages: 1-14

    • DOI

      10.1038/ncomms7329

    • Related Report
      2015 Annual Research Report 2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Autoantigen BiP-derived HLA-DR4 epitopes differentially recognized by effector and regulatory T cells in rheumatoid arthritis.2015

    • Author(s)
      Shoda H, Fujio K, Sakurai K, Ishigaki K, Nagafuchi Y, Shibuya M, Sumitomo S, Okamura T, Yamamoto K
    • Journal Title

      Arthritis and Rheumatology

      Volume: in press Issue: 5 Pages: 1171-81

    • DOI

      10.1002/art.39054

    • Related Report
      2015 Annual Research Report 2014 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Interleukin-27 in T cell immunity.2015

    • Author(s)
      Iwasaki Y, Fujio K, Okamura T, Yamamoto K
    • Journal Title

      Int J Mol Sci

      Volume: 16 Issue: 2 Pages: 2851-63

    • DOI

      10.3390/ijms16022851

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Genetics of rheumatoid arthritis contributes to biology and drug discovery.2014

    • Author(s)
      Okada Y, Wu D, Trynka G, Raj T, Terao C, Ikari K, Kochi Y, Ohmura K, Suzuki A, Yoshida S, Graham RR, Manoharan A, Ortmann W, Bhangale T, Denny JC, (省略), GARNET consortium, (以下省略).
    • Journal Title

      Nature

      Volume: 506 Issue: 7488 Pages: 376-381

    • DOI

      10.1038/nature12873

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] PAD4 regulates proliferation of multipotent hematopoietic cells by controlling c-myc expression.2013

    • Author(s)
      Nakashima K, Arai1 S, Suzuki A, Nariai Y, Urano T, Nakayama M, Ohara O, Yamamura K, Yamamoto K, Miyazaki T.
    • Journal Title

      Nature Communications.

      Volume: 4 Issue: 1 Pages: 1836-1836

    • DOI

      10.1038/ncomms2862

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Egr2 and Egr3 are the unique regulators for systemic autoimmunity.2013

    • Author(s)
      Sumitomo S, Fujio K, Okamura T, Yamamoto K.
    • Journal Title

      JAKSTAT

      Volume: 2 Issue: 2 Pages: e23952-e23952

    • DOI

      10.4161/jkst.23952

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Alendronate attenuates eosinophilic airway inflammation associated with suppression of Th2 cytokines, Th17 cytokines, and eotaxin-2.2013

    • Author(s)
      Oh Sasaki, Mitsuru Imamura, Yusuke Yamazumi, Hiroaki Harada, Taku Matsumoto, Katsuhide Okunishi, Kazuyuki Nakagome, Ryoichi Tanaka, Tetsu Akiyama, Kazuhiko Yamamoto and Makoto Dohi
    • Journal Title

      J. Immunol

      Volume: 191 Issue: 6 Pages: 2879-2889

    • DOI

      10.4049/jimmunol.1300460

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Transcription factor early growth response 3 is associated with the TGF-β1 expression and the regulatory activity of CD4-positive T cells in vivo.2013

    • Author(s)
      Sumitomo S, Fujio K, Okamura T, Morita K, Ishigaki K, Suzukawa K, Kanaya K, Kondo K, Yamasoba T, Furukawa A, Kitahara N, Shoda H, Shibuya M, Okamoto A, Yamamoto K.
    • Journal Title

      J Immunol

      Volume: 191 Issue: 5 Pages: 2351-9

    • DOI

      10.4049/jimmunol.1202106

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The power Doppler twinkling artefact associated with periarticular calcification induced by intra-articular corticosteroid injection in patients with rheumatoid arthritis.2013

    • Author(s)
      Nagafuchi Y, Sumitomo S, Soroida Y, Kanzaki T, Iwasaki Y, Michishita K, Iwai T, Ikeda H, Fujio K, Yamamoto K.
    • Journal Title

      Ann Rheum Dis

      Volume: 72 Issue: 7 Pages: 1267-9

    • DOI

      10.1136/annrheumdis-2012-202897

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] An association analysis of HLA-DRB1 with systemic lupus erythematosus and rheumatoid arthritis in a Japanese population: effects of *09:01 allele on disease phenotypes.2013

    • Author(s)
      Shimane K, Kochi Y, Suzuki A, Okada Y, Ishii T, Horita T, Saito K, Okamoto A, Nishimoto N, Myouzen K, Kubo M, Hirakata M, Sumida T, Takasaki Y, Yamada R, Nakamura Y, Kamatani N, Yamamoto K.
    • Journal Title

      Rheumatology (Oxford)

      Volume: 52 Issue: 7 Pages: 1172-82

    • DOI

      10.1093/rheumatology/kes427

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Egr-2 transcription factor is required for Blimp-1 mediated IL-10 production in IL-27 stimulated CD4(+) T cells2013

    • Author(s)
      Iwasaki, Y.
    • Journal Title

      Eur J Immunol

      Volume: undefined Issue: 4 Pages: 1063-73

    • DOI

      10.1002/eji.201242942

    • Related Report
      2013 Annual Research Report 2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Regulatory cell subsets in the control of autoantibody production related to systemic autoimmunity.2013

    • Author(s)
      Fujio K, Okamura T, Sumitomo S, Yamamoto K.
    • Journal Title

      Ann Rheum Dis

      Volume: 72 Pages: 1-8

    • DOI

      10.1136/annrheumdis-2012-202341

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Functional variants in NFKBIE and RTKN2 involved in activation of the NF-κB pathway are associated with rheumatoid arthritis in Japanese.2012

    • Author(s)
      Myouzen K, Kochi Y, Okada Y, Terao C, Suzuki A et al.
    • Journal Title

      PLoS Genet

      Volume: 8 Issue: 9 Pages: e1002949-e1002949

    • DOI

      10.1371/journal.pgen.1002949

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Meta-analysis identifies nine new loci associated with rheumatoid arthritis in the Japanese population2012

    • Author(s)
      Okada Y, Terao C, Ikari K, Kochi Y, Ohmura K, Suzuki A, Kawaguchi T, Stahl EA, Kurreeman FA, Nishida N, Ohmiya H, Myouzen K, Takahashi M, Sawada T, Nishioka Y, Yukioka M, Matsubara T, Wakitani S, Teshima R, Tohma S, Takasugi K, Shimada K, Murasawa A, Honjo S, Matsuo K, Tanaka H, Tajima K, Suzuki T, Iwamoto T, Kawamura Y, Tanii H, Okazaki Y, Sasaki T, Gregersen PK, Padyukov L, Worthington J, Siminovitch KA, Lathrop M, Taniguchi A, Takahashi A, Tokunaga K, Kubo M, Nakamura Y, Kamatani N, Mimori T, Plenge RM, Yamanaka H, Momohara S, Yamada R, Matsuda F, Yamamoto K.
    • Journal Title

      Nat Genet.

      Volume: (in press) Issue: 5 Pages: 511-6

    • DOI

      10.1038/ng.2231

    • Related Report
      2012 Annual Research Report 2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A genome-wide association study identified AFF1 as a susceptibility locus for systemic lupus eyrthematosus in Japanese2012

    • Author(s)
      岡田随象
    • Journal Title

      PLoS Genetics

      Volume: (掲載確定) Issue: 1 Pages: 1002455-1002455

    • DOI

      10.1371/journal.pgen.1002455

    • NAID

      120005906866

    • Related Report
      2012 Annual Research Report 2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Regulation of histone modification and chromatin structure by the p53-PADI4 pathway2012

    • Author(s)
      Tanikawa C, Espinosa M, Suzuki A, Masuda K, Yamamoto K, Tsuchiya E, Ueda K, Daigo Y, Nakamura Y, Matsuda K.
    • Journal Title

      Nat Commun.

      Volume: 3 Issue: 1 Pages: 676-676

    • DOI

      10.1038/ncomms1676

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] PADI4 polymorphism predisposes male smokers to rheumatoid arthritis2011

    • Author(s)
      Kochi Y, Thabet MM, Suzuki A, Okada Y, Daha NA, Toes REM, Huizinga TWJ, Myouzen K, Kubo M, Yamada R, Nakamura Y, Yamamoto K.
    • Journal Title

      Ann Rheum Dis

      Volume: 70 Issue: 3 Pages: 512-5

    • DOI

      10.1136/ard.2010.130526

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Presentation] Genetics of Rheumatoid Arthritis2016

    • Author(s)
      山本 一彦
    • Organizer
      18th Conference on Advances in Targeted Therapies(ATT)
    • Place of Presentation
      Palma ,Spain
    • Year and Date
      2016-03-18
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Genetics of rheumatic diseases2016

    • Author(s)
      山本 一彦
    • Organizer
      IRA - APLAR COURSE ON RHEUMATOLOGY
    • Place of Presentation
      Jakarta, Indonesia
    • Year and Date
      2016-02-24
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Genetics and Epigenetics of Rheumatoid Arthritis2015

    • Author(s)
      山本 一彦
    • Organizer
      The 17th Asia Pacific League of Associations for Rheumatology Congress
    • Place of Presentation
      Chenna,iIndia
    • Year and Date
      2015-09-06
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Regulatory T cells in human diseases2015

    • Author(s)
      山本 一彦
    • Organizer
      11th International Congress on Systemic Lupus Erythematosus
    • Place of Presentation
      Vienna,Austria
    • Year and Date
      2015-09-01
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] A novel regulatory T cell subset controlling B cell functions: a combination of therapeutic cytokines2015

    • Author(s)
      山本 一彦
    • Organizer
      7th International Forum on Rheumatoid Arthritis (IFRA)
    • Place of Presentation
      北京,中国
    • Year and Date
      2015-08-29
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] CD4+CD25-LAG3+ Regulatory T Cells Control B Cell Responses2014

    • Author(s)
      山本一彦
    • Organizer
      The Immune system in health and disease
    • Place of Presentation
      ハイデルベルグ(ドイツ)
    • Year and Date
      2014-12-08
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] Current and future genetics of rheumatoid arthritis in Asia2014

    • Author(s)
      山本一彦
    • Organizer
      The 59th Annual Meeting of the Japan Society of Human Genetics
    • Place of Presentation
      東京(日本)
    • Year and Date
      2014-11-19 – 2014-11-22
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] A brief history of GWAS and next generation genetics of RA2014

    • Author(s)
      山本一彦
    • Organizer
      Rheumatoid arthritis genetics meeting
    • Place of Presentation
      ボストン(米国)
    • Year and Date
      2014-11-16
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] TGF-beta3-Producing CD4+CD25-LAG3+ Regulatory T Cells Control B Cell Responses2014

    • Author(s)
      山本一彦
    • Organizer
      Cold Spring Habor Asia 2014
    • Place of Presentation
      上海(中国)
    • Year and Date
      2014-09-02 – 2014-09-06
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] Genetics is a fundamental of epigenetics in autoimmune diseases2014

    • Author(s)
      山本一彦
    • Organizer
      The 58th Annual Meeting of Japan College of Rheumatology
    • Place of Presentation
      東京(日本)
    • Year and Date
      2014-04-24 – 2014-04-26
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] From Genetics to Functional Insights into the Pathogenesis of Rheumatoid Arthritis

    • Author(s)
      山本一彦
    • Organizer
      Advances in Targeted Therapies(招待講演)
    • Place of Presentation
      ニース
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] From Genetics to Functional Insights into the Pathogenesis of Rheumatoid arthritis

    • Author(s)
      山本一彦
    • Organizer
      APLAR(招待講演)
    • Place of Presentation
      バリ
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] Genetics of Rheumatoid Arthritis:Functional insights into the pathogenesis

    • Author(s)
      山本一彦
    • Organizer
      Karolinska大学(招待講演)
    • Place of Presentation
      スウェーデン
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] From Genetics to Functional Insights of Autoimmune Diseases

    • Author(s)
      山本一彦
    • Organizer
      Taiwan Rheumatology Forum(招待講演)
    • Place of Presentation
      台湾
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] Novel Regulatory T cells controlling autoantibody production

    • Author(s)
      山本一彦
    • Organizer
      ACA香港(招待講演)
    • Place of Presentation
      香港
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Remarks] 東京大学医学部附属病院 アレルギーリウマチ内科 第18研究室

    • URL

      http://plaza.umin.ac.jp/areriu18/

    • Related Report
      2014 Annual Research Report
  • [Patent(Industrial Property Rights)] B細胞活性化の抑制剤及び自己免疫疾患の治療剤2014

    • Inventor(s)
      山本一彦ほか5名
    • Industrial Property Rights Holder
      国立大学法人東京大学
    • Industrial Property Rights Type
      特許
    • Filing Date
      2014-11-28
    • Related Report
      2014 Annual Research Report

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Published: 2011-06-18   Modified: 2019-07-29  

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