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The role of innate immunology in the patients with early rheumatoid arthritis and resistant-anti rheumatic drugs

Research Project

Project/Area Number 17K10995
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Orthopaedic surgery
Research InstitutionYamagata University

Principal Investigator

Takakubo Yuya  山形大学, 医学部, 准教授 (80431641)

Co-Investigator(Kenkyū-buntansha) 高木 理彰  山形大学, 医学部, 教授 (40241707)
佐々木 幹  山形大学, 医学部, 非常勤講師 (00444034)
長沼 靖  山形大学, 医学部, 客員研究員 (10463811)
大木 弘治  山形大学, 医学部, 非常勤講師 (20463812)
Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2017: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Keywords関節リウマチ / 薬剤耐性 / 自然免疫 / Toll様受容体 / 制御性免疫 / 獲得免疫 / 炎症性免疫担当細胞 / 炎症性サイトカイン / 疾患活動性 / グレード分類 / 薬剤抵抗性 / 免疫学 / 薬剤反応性
Outline of Final Research Achievements

The aim of this study was to investigate the immuneinflammatory cells, including Toll-like receptors (TLRs)- equipped cells, in synovial tissue and fluid samples from the patients with early and established rheumatoid arthritis (RA) with/without treatment of synthetic disease-modifying antirheumatic drug (sDMARD) including biologics.
T and B cell counts were lower in the biologics than in the csDMARD group (p<0.05). In contrast, the C-reactive protein (CRP) and disease activity score DAS28-CRP did not show clear-cut correlations with the inflammatory grade of the synovitis. Similar numbers of cells immunoreactive for TLR-1 to TLR-9 were found in synovitis in both groups.
Patients clinically responding to biologics might still have the potential of moderate/severe local joint inflammation, composed in particular of and possibly driven by the autoinflammatory TLR+ cells.

Academic Significance and Societal Importance of the Research Achievements

関節リウマチに対する適切な治療介入により,自然免疫,獲得免疫とも抑制され,制御性免疫細胞が増加する傾向がみられたが,Toll様受容体陽性細胞を中心に,自然免疫系反応が残存しやすいことが示唆された。
今後,従来型の疾患修飾性抗リウマチ薬や生物学的製剤,分子標的型合成抗リウマチ薬を用いても症状の寛解が得られない患者では,自然免疫系反応をターゲットとした治療が重要になると結論づけられた。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (50 results)

All 2020 2019 2018 2017 Other

All Int'l Joint Research (6 results) Journal Article (13 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 13 results,  Open Access: 4 results) Presentation (30 results) (of which Int'l Joint Research: 17 results) Book (1 results)

  • [Int'l Joint Research] スタンフォード大学/Stuart Goodman教授(米国)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] ヘルシンキ大学/Kari Eklund教授(フィンランド)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] Stanford University(米国)

    • Related Report
      2018 Research-status Report
  • [Int'l Joint Research] Helsinki University(フィンランド)

    • Related Report
      2018 Research-status Report
  • [Int'l Joint Research] Helsinki University(FINLAND)

    • Related Report
      2017 Research-status Report
  • [Int'l Joint Research] Stanford University(米国)

    • Related Report
      2017 Research-status Report
  • [Journal Article] Comparative study of HO-1 expressing synovial lining cells between RA and OA2020

    • Author(s)
      Yang Suran、Ohe Rintaro、Aung Naing Ye、Kato Tomoya、Kabasawa Takanobu、Utsunomiya Aya、Takakubo Yuya、Takagi Michiaki、Yamakawa Mitsunori
    • Journal Title

      Modern Rheumatology

      Volume: - Issue: 1 Pages: 1-8

    • DOI

      10.1080/14397595.2019.1704976

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] intestinal immunity and flora in a collagen-induced mouse parthritis model: differences during arthritis progression.2019

    • Author(s)
      Nemoto N, Takeda Y, Nara H, Araki A, Gazi Y, Takakubo Y, Naganuma Y, Takagi M, Asao H
    • Journal Title

      Int Immunol.

      Volume: 32 Issue: 1 Pages: 49-56

    • DOI

      10.1093/intimm/dxz058

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Rapid disappearing of gouty tophi of foot due to reducing urate pool by resection of huge gouty tophi of opposite foot in the patient with hyperuricemia; a case of report.2019

    • Author(s)
      Takakubo Y, Imamura Y, Tezuka H, Okada S, Naganuma Y, Ito J, Sugawara M, Yang S, Oki H, Sasaki A, Sasaki K, Takagi M
    • Journal Title

      Modern Rheumatology Case Reports

      Volume: 4 Issue: 1 Pages: 1-6

    • DOI

      10.1080/24725625.2019.1680135

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Assessing an alpha-defensin lateral flow device for diagnosing septic arthritis: reporting on a false-negative case and a false-positive case.2019

    • Author(s)
      2.Narita A, Suzuki A, Nakajima T, Takakubo Y, Ito J, Sasaki A, Takagi M
    • Journal Title

      Modern Rheumatology Case Reports.

      Volume: 4 Issue: 1 Pages: 156-160

    • DOI

      10.1080/24725625.2019.1683134

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Disassembly of bilateral bipolar heads within 10 years after hip hemiarthroplasties for avascular necrosis of femoral heads: a case report.2019

    • Author(s)
      Ito J, Takakubo Y, Monma R, Oki H, Sasaki K, Takagi M
    • Journal Title

      Modern Rheumatology Case Reports.

      Volume: 4 Issue: 1 Pages: 147-151

    • DOI

      10.1080/24725625.2019.1662596

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] 生物学的製剤使用関節リウマチ患者における整形外科手術の検討.2019

    • Author(s)
      高窪祐弥, 大木弘治, 長沼靖、梁秀蘭、高木理彰
    • Journal Title

      関節の外科

      Volume: 45 Pages: 101-104

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Activation of plasmacytoid dendritic cells by apoptotic particles - mechanism for the loss of immunological tolerance in Sj&ouml;gren's syndrome.2018

    • Author(s)
      Ainola M, Porola P, Takakubo Y, Przybyla B, Kouri VP, Tolvanen TA, H&auml;nninen A, Nordstr&ouml;m DC.
    • Journal Title

      Clin Exp Immunol.

      Volume: 191 Issue: 3 Pages: 301-310

    • DOI

      10.1111/cei.13077

    • Related Report
      2018 Research-status Report 2017 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Immunohistochemical Analysis of Inflammatory Rheumatoid Synovial Tissues Using Anti-Human Podoplanin Monoclonal Antibody Panel.2018

    • Author(s)
      Suzuki T, Takakubo Y, Oki H, Liu X, Honma R, Naganuma Y, Goodman SB, Kaneko MK, Kato Y, Takagi M.
    • Journal Title

      Monoclon Antib Immunodiagn Immunother.

      Volume: 37 Issue: 1 Pages: 12-19

    • DOI

      10.1089/mab.2017.0047

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Danger of frustrated sensors: Role of Toll-like receptors and NOD-like receptors in aseptic and septic inflammations around total hip replacements.2017

    • Author(s)
      Takagi M, Takakubo Y, Pajarinen J, Naganuma Y, Oki H, Masahiro M, Goodman S
    • Journal Title

      J Orthop Translat

      Volume: 10 Issue: 3 Pages: 1-8

    • DOI

      10.1016/j.jos.2018.01.016

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Danger of frustrated sensors: Role of TLR and NOD-like receptors in aseptic and septic inflammations around failed total hip replacements2017

    • Author(s)
      Takagi M, Takakubo Y, et al.
    • Journal Title

      J Orthop Translat

      Volume: 10 Pages: 68-85

    • DOI

      10.1016/j.jot.2017.05.004

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Distribution of podoplanin in synovial tissues in rheumatoid arthritis patients using biologic or conventional disease-modifying anti-rheumatic drugs.2017

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

      Curr Rheumatol Rev.

      Volume: 13 Issue: 1 Pages: 72-78

    • DOI

      10.2174/1573397112666160331143607

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] The Incidence of Atypical Femoral Fractures in Patients with Rheumatic Disease: Yamagata Prefectural Committee of Atypical Femoral Fractures (YamaCAFe) Study2017

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

      The Tohoku Journal of Experimental Medicine

      Volume: 242 Issue: 4 Pages: 327-334

    • DOI

      10.1620/tjem.242.327

    • NAID

      130006067688

    • ISSN
      0040-8727, 1349-3329
    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Comparison of the Effects of Osteochondral Autograft Transplantation With Platelet-Rich Plasma or Platelet-Rich Fibrin on Osteochondral Defects in a Rabbit Model.2017

    • Author(s)
      Maruyama M, Takakubo Y, et al.
    • Journal Title

      Am J Sports Med.

      Volume: 45 Issue: 14 Pages: 3280-3288

    • DOI

      10.1177/0363546517721188

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Presentation] Distrbution of Toll-like receptors expressing immune-cells in rheumatoid synovial tissues of the patients who received CTLA4-Ig agent.2019

    • Author(s)
      1.Takakubo Y, Oki H, Yang S, Sasaki A, Sasaki K, Naganuma Y, KatoY, Takagi M
    • Organizer
      ORS 2019 Annual Meeting
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Anti-tumor necrosis factor agents influence the apoptosis of inflammatory synovial cells in the patients with rheumatoid arthritis.2019

    • Author(s)
      Takakubo Y, Suzuki Y, Yang S, Oki H, Takagi M
    • Organizer
      The 2nd International Combined Meeting of Orthopaedic Reserch Societies
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Rehabilitation of the salvege arthrodesis with bone auto- and allografts for failed total ankle arthroplasties in the patient with rheumatoid arthritis.2019

    • Author(s)
      Takakubo Y, Narita A, Takano M, Suzuki Y, Sasaki K, Ito J, Sagae H, Kanauchi Y, Kobayashi S, Takagi M
    • Organizer
      56th Annual Meeting of Japanese Association of Rehabilitation Medicine
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Induction of podoplanin in synovial lining cell of lipopolysaccharide-induced rabbit arthritis model.2019

    • Author(s)
      Honma R, Maruyama M, Liu X, Oki H, Takakubo Y, Takagi M
    • Organizer
      The 2nd International Combined Meeting of Orthopaedic Reserch Societies
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Podoplanin is a potential biomarker in lipopolysaccharide-induced inflamed human fibroblast-like synoviocytes.2019

    • Author(s)
      Suzuki T, Liu X, Takakubo Y, Oki H**, Honma R, Takagi M
    • Organizer
      The 2nd International Combined Meeting of Orthopaedic Reserch Societies
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Radiographic joint destruction in the patients with rheumatoid arthritis who have withdrawn, spaced or continued biologics after reaching remission from local biologics registry.2019

    • Author(s)
      Nagai J, Takakubo Y, Yang S, Suzuki Y, Sasaki A**, Oki H**, Naganuma Y**, Sasaki K**, Takagi M
    • Organizer
      The 92nd Annual Meeting of the Japanese Orthopaedic Association
    • Related Report
      2019 Annual Research Report
  • [Presentation] Utility of alpha-defesin lateral flow device for periprosthetic joint onfection and septic arthritis.2019

    • Author(s)
      Narita A, Suzuki A, Nakajima, Takakubo Y, Ito J, Yuki I, Oki H, Naganuma Y, Takagi M
    • Organizer
      ORS 2019 Annual Meeting
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Distribution of Toll-like receptors expressing immune-cells in rheumatoid synovial tissues of the patients who received CTLA4-Ig agent.2019

    • Author(s)
      Takakubo Y, Oki H, Yang S, et al:
    • Organizer
      ORS 2019
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] The Value of Serum Interleukin-6 Before First Biologis Are Predicted to Clinical Response in The Patients of Rheumatoid Arthritis One Year After The Treatment.2018

    • Author(s)
      Takakubo Y, Oki H, Sasaki K, et al:
    • Organizer
      ORS 2018
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Analysis of radiographic joint destruction in rheumatoid patients who have withdrawn, spaced and continued of biologics after achieving sustained remission from local biologics registry.2018

    • Author(s)
      Takakubo Y, Nagai J, Naganuma Y, et al.
    • Organizer
      European League Against Rheumatism 2018
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Changing of Orthopaedics Surgeries for the Patients with Rheumatoid Arthritis in BIO-era.2018

    • Author(s)
      Takakubo Y, Ito J, Oki H, et al
    • Organizer
      91th Annual Meeting of JOA
    • Related Report
      2018 Research-status Report
  • [Presentation] The trend of primary total hip arthroplasties for the patients with osteoarthritis in super-aging area in last thirteen years.2018

    • Author(s)
      Takakubo Y, Ito J, Oki H, et al
    • Organizer
      91th Annual Meeting of JOA
    • Related Report
      2018 Research-status Report
  • [Presentation] Mid- and long-term results of revision THA with KT-plate for acetabular reconstruction.2018

    • Author(s)
      Takakubo Y, Kawaji H, Ito J, et al
    • Organizer
      91th Annual Meeting of JOA
    • Related Report
      2018 Research-status Report
  • [Presentation] Tumor necrosis factor inhibitors influence the apoptosis of inflammatory cells in rheumatoid synovial tissues.2018

    • Author(s)
      Takakubo Y, Oki H, Sasaki K
    • Organizer
      62th Annual Meeting of Japan College of Rheumatology
    • Related Report
      2018 Research-status Report
  • [Presentation] Foot and ankle surgeries for the patients with rheumatoid arthritis in BIO-era.2018

    • Author(s)
      Takakubo Y, Oki H, Sasaki K
    • Organizer
      62th Annual Meeting of Japan College of Rheumatology
    • Related Report
      2018 Research-status Report
  • [Presentation] Bone healing of atypical femoral fractures which were treated by teriparatide and low intensity pulsed ultrasound therapy in the patients with rheumatic diseases in the highly super aging area of North Japan.2018

    • Author(s)
      Takakubo Y, Miyaji T, Ota D, et al.
    • Organizer
      Scandinavian Congress of Rheumatology
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Infections are increased as the cause of revision total hip arthroplasties in the super-aging area in Northern Japan.2018

    • Author(s)
      Takakubo Y, Ito J, Oki H, et al
    • Organizer
      EORS
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Expression of inflammatory cytokines from plasmacytoid dendritic cells by stimulation of microparticles2018

    • Author(s)
      Takakubo Y, Ainola M, Oki H, et al
    • Organizer
      33th Annual Research Meeting of JOA
    • Related Report
      2018 Research-status Report
  • [Presentation] Toll-like receptors and immune-cells in rheumatoid synovial tissues treated by tocilizumab (TCZ)2018

    • Author(s)
      Takakubo Y, Suzuki T, Oki H, et al
    • Organizer
      4th Japan Society of Osteoimmunology
    • Related Report
      2018 Research-status Report
  • [Presentation] The role of innate sensors in aseptic and septic loosening of total joint arthroplasty.2017

    • Author(s)
      Takakubo Y, et al.
    • Organizer
      Orthopaedic surgery meeting at UCSF
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] The role of innate sensors in aseptic and septic loosening of total joint arthroplasty.2017

    • Author(s)
      Takakubo Y, et al.
    • Organizer
      Orthopaedic surgery meeting at Stanford University
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] The role of innate sensors in aseptic and septic loosening of total joint arthroplasty.2017

    • Author(s)
      Takakubo Y, et al.
    • Organizer
      Ground raound of Orthopaedic surery at Utah University
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] High-Molecular-Weight adiponectin is correlated with disease activity in the patients with rheumatoid arthritis.2017

    • Author(s)
      Takakubo Y, et al.
    • Organizer
      Orthopaedic Research Society 2017 Annual Meeting
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Is increasing the trend of primary total hip arthroplasties for the patients with osteoarthritis, but decreasing the rate of female in super-aging area of Japan in last twelve years?2017

    • Author(s)
      Takakubo Y, et al.
    • Organizer
      EULAR 2017
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Postoperative rehabilitation of atypical femoral fractures in patients with rheumatic diseases.2017

    • Author(s)
      Takakubo Y, et al.
    • Organizer
      The 54th Annual meeting of the Japanese association of rhehabilitation medicine
    • Related Report
      2017 Research-status Report
  • [Presentation] Expression of podoplanin in synovial tissue of rheumatoid arthritis.2017

    • Author(s)
      Takakubo Y, et al.
    • Organizer
      The 61th Annual General Assembly and Scientific Meeting of the Japan College of Rheumatology
    • Related Report
      2017 Research-status Report
  • [Presentation] Trend of atypical femoral fractures in rheumatic patients in the highly super aging area of North Japan.2017

    • Author(s)
      Takakubo Y, et al.
    • Organizer
      The 61th Annual General Assembly and Scientific Meeting of the Japan College of Rheumatology
    • Related Report
      2017 Research-status Report
  • [Presentation] Trend of orthopaedic surgeries for the patients with rheumatoid arthritis who are received biologic agents in our institute.2017

    • Author(s)
      Takakubo Y, et al.
    • Organizer
      The 90th Annual Meeting of the Japanese Orthopaedic Association
    • Related Report
      2017 Research-status Report
  • [Presentation] The incidence of atypical femoral fractures in patients with rheumatic disease in our prefectural area of north Japan in the suger-aging society: YamaCAFe study.2017

    • Author(s)
      Takakubo Y, et al.
    • Organizer
      The 90th Annual Meeting of the Japanese Orthopaedic Association
    • Related Report
      2017 Research-status Report
  • [Presentation] Trend of total hip arthroplasties in the super-aging area in Northern Japan.2017

    • Author(s)
      Takakubo Y, et al.
    • Organizer
      ISTA 2017
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Book] 変形性関節症(股関節)の手術療法 ~骨切り術から人工股関節置換術まで~2017

    • Author(s)
      高窪祐弥, 佐々木幹, 高木理彰
    • Total Pages
      9
    • Publisher
      Pharma Medica
    • Related Report
      2017 Research-status Report

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Published: 2017-04-28   Modified: 2022-02-21  

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