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Basic research for searching of new therapeutic targets of rheumatoid arthritis through investigation of novel action of CTLA-4-Ig

Research Project

Project/Area Number 15K09531
Research Category

Grant-in-Aid for Scientific Research (C)

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

Principal Investigator

KAWAKAMI Atsushi  長崎大学, 医歯薬学総合研究科(医学系), 教授 (90325639)

Co-Investigator(Kenkyū-buntansha) 岩本 直樹  長崎大学, 医歯薬学総合研究科(医学系), 助教 (80437897)
一瀬 邦弘  長崎大学, 医歯薬学総合研究科(医学系), 講師 (60437895)
古賀 智裕  長崎大学, 医歯薬学総合研究科(医学系), 助教 (90537284)
右田 清志  福島県立医科大学, 医学部, 教授 (60264214)
中村 英樹  長崎大学, 病院(医学系), 講師 (10437832)
佐々木 均  長崎大学, 病院(医学系), 教授 (00170689)
Project Period (FY) 2015-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywords関節リウマチ / CTLA-4-Ig / バイオマーカー / 単球 / M1・M2 / 破骨細胞 / 骨破壊 / ACPA / サイトカイン・ケモカイン / 滑膜線維芽細胞 / ACPA-サブクラス / CTLA-4Ig / リバースシグナル / アレイ解析 / 関節超音波
Outline of Final Research Achievements

Peripheral blood (PB) CD14+ monocytes from ACPA-positive RA patients were M1 phenotype-dominant and osteoclastic differentiation was also facilitated. CTLA-4-Ig inhibited the process and the related gene expression patterns were observed. Activation of osteoclastic differentiation in collagen-induced arthritis was significantly inhibited by chemical inhibitor of CaMK4, and these processes were also found in PB CD14+ monocytes from RA patients. These data indicate the existence of cross-talk among CTLA-4-Ig, CaMK4 and ACPA. In human sera study, we have focused on the ACPA titer change in abatacept-treated RA patients and found that early reduction ACPA titer reflects the efficacy at 12 months. The changes of serum biomarkers are different among RA patients treated by abatacept, TNF inhibitor and IL-6 inhibitor, thus, we have been investigating the next-stage therapeutic targets through search of integrated analysis including CTLA-4-Ig-specific pathways.

Academic Significance and Societal Importance of the Research Achievements

CTLA-4-Igの作用機序とkey moleculesをin vitro細胞培養研究、疾患モデル動物研究、ヒトRA検体を用いた研究から解析し、抗CCP抗体(ACPA)陽性患者におけるM1単球分化異常、CTLA-4-Ig、ACPA、CaMK4の相互作用が強く示唆されることを明らかとした。RA血清検体ではCTLA-4-Ig、TNF阻害、IL-6阻害において、特に前2者ではACPAを軸とした評価で反応が異なることを示し、CTLA-4-Igに特徴的なシグナルの解析は次世代の治療標的の探索に繋がることを示した。

Report

(5 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • 2015 Research-status Report
  • Research Products

    (28 results)

All 2018 2017 2016 2015

All Journal Article (11 results) (of which Int'l Joint Research: 6 results,  Peer Reviewed: 11 results,  Open Access: 8 results) Presentation (17 results) (of which Int'l Joint Research: 10 results)

  • [Journal Article] Osteogenic differentiation of fibroblast-like synovial cells in rheumatoid arthritis is induced by microRNA-218 through a ROBO/Slit pathway2018

    • Author(s)
      Iwamoto Naoki、Fukui Shoichi、Takatani Ayuko、Shimizu Toshimasa、Umeda Masataka、Nishino Ayako、Igawa Takashi、Koga Tomohiro、Kawashiri Shin-ya、Ichinose Kunihiro、Tmai Mami、Nakamura Hideki、Origuchi Tomoki、Chiba Ko、Osaki Makoto、J?ngel Astrid、Gay Steffen、Kawakami Atsushi
    • Journal Title

      Arthritis Research & Therapy

      Volume: 20 Issue: 1 Pages: 189-189

    • DOI

      10.1186/s13075-018-1703-z

    • NAID

      120006987960

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Ultrasonographic efficacy of biologic and targeted synthetic DMARDs therapy in RA from multicenter RA ultrasound prospective cohort in Japan2018

    • Author(s)
      Nishino Ayako、Kawashiri Shin-ya、Koga Tomohiro、Iwamoto Naoki、Ichinose Kunihiro、Tamai Mami、Nakamura Hideki、Origuchi Tomoki、Ueki Yukitaka、Yoshitama Tamami、Eiraku Nobutaka、Matsuoka Naoki、Okada Akitomo、Fujikawa Keita、Hamada Hiroaki、Tsuru Tomomi、Nagano Shuji、Arinobu Yojiro、Hidaka Toshihiko、Kawakami Atsushi
    • Journal Title

      Arthritis Care & Research

      Volume: 26 Issue: 12 Pages: 1719-1726

    • DOI

      10.1002/acr.23551

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] M1 and M2 Monocytes in Rheumatoid Arthritis: A Contribution of Imbalance of M1/M2 Monocytes to Osteoclastogenesis2018

    • Author(s)
      Fukui Shoichi、Iwamoto Naoki、Takatani Ayuko、Igawa Takashi、Shimizu Toshimasa、Umeda Masataka、Nishino Ayako、Horai Yoshiro、Hirai Yasuko、Koga Tomohiro、Kawashiri Shin-ya、Tamai Mami、Ichinose Kunihiro、Nakamura Hideki、Origuchi Tomoki、Masuyama Ritsuko、Kosai Kosuke、Yanagihara Katsunori、Kawakami Atsushi
    • Journal Title

      Frontiers in Immunology

      Volume: 8 Pages: 1958-1958

    • DOI

      10.3389/fimmu.2017.01958

    • NAID

      120006987316

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The role of CaMK4 in immune responses2017

    • Author(s)
      Koga Tomohiro、Kawakami Atsushi
    • Journal Title

      Modern Rheumatology

      Volume: 28 Issue: 2 Pages: 211-214

    • DOI

      10.1080/14397595.2017.1413964

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] MicroRNA-204-3p inhibits lipopolysaccharide-induced cytokines in familial Mediterranean fever via the phosphoinositide 3-kinase γ pathway2017

    • Author(s)
      Koga Tomohiro,Migita Kiyoshi,Sato Tomohito,Sato Shuntaro,Umeda Masataka,Nonaka Fumiaki,Fukui Shoichi,Kawashiri Shin-ya,Iwamoto Naoki,Ichinose Kunihiro,Tamai Mami,Nakamura Hideki,Origuchi Tomoki,Ueki Yukitaka,Masumoto Junya,Agematsu Kazunaga,Yachie Akihiro,Yoshiura Koh-ichiro,Eguchi Katsumi,Kawakami Atsushi
    • Journal Title

      Rheumatology

      Volume: 57 Issue: 4 Pages: 718-726

    • DOI

      10.1093/rheumatology/kex451

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Comparison of serum inflammatory cytokine concentrations in familial Mediterranean fever and rheumatoid arthritis patients2017

    • Author(s)
      Koga T、Kawashiri S-y、Migita K、Sato S、Umeda M、Fukui S、Nishino A、Nonaka F、Iwamoto N、Ichinose K、Tamai M、Nakamura H、Origuchi T、Ueki Y、Masumoto J、Agematsu K、Yachie A、Eguchi K、Kawakami A
    • Journal Title

      Scandinavian Journal of Rheumatology

      Volume: - Issue: 4 Pages: 1-3

    • DOI

      10.1080/03009742.2017.1363281

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] TNF-α-induced miR-155 regulates IL-6 signaling in rheumatoid synovial fibroblasts2017

    • Author(s)
      Migita Kiyoshi、Iwanaga Nozomi、Izumi Yasumori、Kawahara Chieko、Kumagai Kenji、Nakamura Tadashi、Koga Tomohiro、Kawakami Atsushi
    • Journal Title

      BMC Research Notes

      Volume: 10 Issue: 1 Pages: 403-403

    • DOI

      10.1186/s13104-017-2715-5

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Baseline MRI bone erosion predicts the subsequent radiographic progression in early rheumatoid arthritis patients who achieved sustained good clinical response.2017

    • Author(s)
      Tamai M, Arima K, Nakashima Y, Kita J, Umeda M, Fukui S, Nishino A, Suzuki T, Horai Y, Okada A, Koga T, Kawashiri SY, Iwamoto N, Ichinose K, Yamasaki S, Nakamura H, Origuchi T, Aoyagi K, Uetani M, Eguchi K, Kawakami A
    • Journal Title

      Mod Rheumatol

      Volume: 印刷中 Issue: 6 Pages: 1-6

    • DOI

      10.1080/14397595.2017.1294280

    • Related Report
      2016 Research-status Report
    • Peer Reviewed
  • [Journal Article] Fewer subsequent relapses and lower levels of IL-17 in Takayasu arteritis developed after the age of 40 years.2016

    • Author(s)
      Fukui S, Iwamoto N, Shimizu T, Umeda M, Nishino A, Koga T, Kawashiri SY, Ichinose K, Hirai Y, Tamai M, Nakamura H, Aramaki T, Iwanaga N, Izumi Y, Origuchi T, Migita K, Ueki Y, Sato S, Kawakami A.
    • Journal Title

      Arthritis Res Ther

      Volume: 13 Issue: 1 Pages: 293-293

    • DOI

      10.1186/s13075-016-1193-9

    • NAID

      120006987596

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] MRI bone oedema at enrollment predicts rapid radiographic progression over 1 year in early rheumatoid arthritis patients: results from the Nagasaki University Early Arthritis Cohort2016

    • Author(s)
      Nakashima Y, Tamai M, Kita J, Michitsuji T, Shimizu T, Fukui S, Umeda M, Nishino A, Suzuki S, Yoshiro Horai, Akitomo Okada, Takayuki Nishimura, Tomohiro Koga, Shin-ya Kawashiri, Naoki Iwamoto, Kunihiro Ichinose, Yasuko Hirai, Arima K, Yamasaki S, Nakamura H, Origuchi T, Takao S, Uetani M, Aoyagi K, Eguchi K, Kawakami A
    • Journal Title

      Journal of Rheumatology

      Volume: 43 Issue: 7 Pages: 7-13

    • DOI

      10.3899/jrheum.150988

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Upregulation of Thrombospondin 1 Expression in Synovial Tissues and Plasma of Rheumatoid Arthritis: Role of Transforming Growth Factor-beta1 toward Fibroblast-like Synovial Cells2015

    • Author(s)
      Suzuki T, Iwamoto N, Yamasaki S, Nishino A, Nakashima Y, Horai Y, Kawashiri S, Y Ichinose K, Arima K, Tamai M, Nakamura H, Origuchi T, Miyamoto C, Osaki M, Ohyama K, Kuroda N, Kawakami A.
    • Journal Title

      Journal of Rheumatology

      Volume: 42 Issue: 6 Pages: 943-947

    • DOI

      10.3899/jrheum.141292

    • Related Report
      2015 Research-status Report
    • Peer Reviewed
  • [Presentation] MicroRNA-887-3p have possibility of downstream effector of MTX in its antiproliferative activity toward fibroblast-like synovial cells in rheumatoid arthritis.2018

    • Author(s)
      Iwamoto N, Tsuji S, Endo Y, Takatani A, Shimizu T, Umeda M, Fukui S, Igawa T,Koga T, Kawashiri S, Ichinose K, Tamai M, Nakamura H, Origuchi T, Kawakami A.
    • Organizer
      20th Asia Pacific League of Associations for Rheumatology Congress
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Combination of Ultrasound Power Doppler-Verfied Synovitis and Seropositivity Accurately Identifies Patients with Early Rheumatoid Arthritis.2018

    • Author(s)
      Kawashiri SY, Fujikawa k, Nishino A, Takatani A, Shimizu T, Umeda M, Fukui S, Igawa T, Koga T, Iwamoto N, Ichinose K, Tamai M, Nakamura H, Origuchi T, Kawakami A.
    • Organizer
      2018 ACR/ARHP Annual Meeting
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] バイオマーカーと超音波指標で解析する関節リウマチにおける生物学的製剤治療の有効性の評価:九州地区多施設共同RA超音波コホート研究2017

    • Author(s)
      川尻真也,西野文子,植木幸孝,榮樂信隆,吉玉珠美,岡田覚丈,松岡直樹,藤川敬太,有信洋二郎,濱田浩朗,日高利彦,永野修司,都留智巳,多田芳史,川上 純.
    • Organizer
      第61回日本リウマチ学会総会・学術集会
    • Related Report
      2017 Research-status Report
  • [Presentation] 関節超音波を用いた生物学的製剤スイッチ例の治療反応評価:九州地区多施設共同RA超音波前方視的コホート研究2017

    • Author(s)
      西野文子,川尻真也,川上 純,植木幸孝.榮樂信隆,吉玉珠美,岡田覚丈,松岡直樹,藤川敬太,有信洋二郎,濱田浩朗,日高利彦,永野修司,都留智巳,多田芳史.
    • Organizer
      第61回日本リウマチ学会総会・学術集会
    • Related Report
      2017 Research-status Report
  • [Presentation] A Novel Concept of M1 and M2 Monocytes in Rheumatoid Arthritis: Pro-inflammatory Monocyte Polarization Imbalance, Anti-Cirtrullinated protein Antibody and Osteoclastogenesis2017

    • Author(s)
      Fukui S, Iwamoto N, Masuyama R, Kosai K, Yanagihara K, Kawakami A.
    • Organizer
      Annual European Congress of Rheumatology
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] miR-204-3P Inhibits The pruduction of TLR-Related Cytokines in Familial Mediterranean Fever By Targeting The Pik3 Signaling2017

    • Author(s)
      Koga T, Migita K, Umeda M, Nonaka F, Kawashiri SY, Iwamoto N, Ichinose K, Tamai M, Origuchi T, Eguchi K, Kawakami A.
    • Organizer
      Annual European Congress of Rheumatology
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Microrna Profiling of MTX-Treated Fibroblast-like Synovial cells in Rheumatoid Arthritis Revealed a Possibility of MICRORNA-887-3P as Novel Therapeutic Target of RA2017

    • Author(s)
      Iwamoto N, Fukui S, Koga T, Kawashiri SY, Ichinose K, Tamai M, Nakamura H, Origuchi T, Kawakami A.
    • Organizer
      Annual European Congress of Rheumatology
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Power Dopper Ultrasonography Detects Superior Efficacy of Non-TNF Biologics Compared to cycling of TNF inhibitors in RA Patients Inadequate Response to First TNF Inhibitors2017

    • Author(s)
      Nishino A, Kawashiri S, Yoshitama T, Eiraku N, Matsuoka N, Ueki Y, Okada A, Hamada H, Hidaka T, Nagao S, Tsuru T, Fujikawa K, Arinubu Y, Tada Y, Nagata Y, Kawakami A.
    • Organizer
      2017 ACR/ARHP Annual Meeting
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Evaluation of Ultrasound-Detecting Efficacy of Abatacept By Profiling Multiple Serum Cytokines, Chemokines and Bone-Related Biomarkers in Rheumatoid Arthritis Ultrasound Prospective Observational Cohort Study2017

    • Author(s)
      Kawashiri S, Nishino A, Eiraku N, Yoshitama T, Matsuoka N, Aramaki T, Ueki Y, Okada A, Hamada H, Nagano S, Fujikawa K, Kawakami A.
    • Organizer
      2017 ACR/ARHP Annual Meeting
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Preferential Distribution of M1 Monocytes in Anti-Cyclic Citrullinated Peptide Antibody Positive Patients with Rheumatoid Arthritis.2016

    • Author(s)
      Fukui S, Iwamoto N, Shimizu T, Umeda M, Nishino A, Horai Y, Koga T, Kawashiri SY, Ichinese K, Hirai Y, Tamai M, Nakamura H, Origuchi T and Kawakami A.
    • Organizer
      ACR/ARHP Annual Meeting 2016
    • Place of Presentation
      ワシントン(米国)
    • Year and Date
      2016-11-11
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] 寛解後の減量・中止における関節エコーの意義2016

    • Author(s)
      川尻真也,青柳 潔,川上 純.
    • Organizer
      第60回日本リウマチ学会総会・学術総会
    • Place of Presentation
      パシフィコ横浜(神奈川県・横浜市)
    • Year and Date
      2016-04-15
    • Related Report
      2016 Research-status Report
  • [Presentation] Ultrasound evaluation of efficacy of biologic and targeted synthetic DMARDs toward rheumatoid arthritis patients:Kyushu multicenter rheumatoid arthritis ultrasound prospective observational cohort in Japan.2016

    • Author(s)
      Nishino A, Kawashiri SY, Kawakami A, Yoshitama T, Eiraku N, Matsuoka N, Ueki Y, Okada A, Hamada T, Fujikawa K, Arinobu Y.
    • Organizer
      第60回日本リウマチ学会総会・学術総会
    • Place of Presentation
      パシフィコ横浜(神奈川県・横浜市)
    • Year and Date
      2016-04-15
    • Related Report
      2016 Research-status Report
  • [Presentation] MRI Bone Oedema at Enrollment Predicts the Development of Rapid Radiographic Progression at 1 year Toward Patients with Early-Stage Rheimatoid Arthritis: Results from Nagasaki University Arthritis Cohort.2015

    • Author(s)
      Nakashima Y,Tamai M, Michitsuji T, Shimizu T, Fukui S, Umeda M, Nishino A, Koga T, Kawashiri S, Iwamoto N, Ichinose K, Hirai Y, Nakamura H, Origuchi T, and Kawakami A.
    • Organizer
      ACR 2015
    • Place of Presentation
      San Francisco (USA)
    • Year and Date
      2015-11-06
    • Related Report
      2015 Research-status Report
    • Int'l Joint Research
  • [Presentation] Ultrasound Evaluation of Efficacy of Biologic and Targeted Synthetic Dmards Toward Rheumatoid Arthritis Patients: Kyushu Multicenter Rheumatoid Arthritis Ultrasound Prospective Observational Cohort in Japan.2015

    • Author(s)
      Nishino A, Kawashiri S, Kawakami A, Yoshitama T, Eiraku N, Matsuoka N, Ueki Y, Okada A, Hamada H, Hidaka T, Nagano S, Tsuru T, Fujikawa K, and Arinobu Y.
    • Organizer
      ACR 2015
    • Place of Presentation
      San Francisco (USA)
    • Year and Date
      2015-11-06
    • Related Report
      2015 Research-status Report
    • Int'l Joint Research
  • [Presentation] 早期関節リウマチにおけるMRIスコアとX線スコアの検討2015

    • Author(s)
      玉井慎美,中島好一,上谷雅孝,川上 純
    • Organizer
      第43回日本臨床免疫学会
    • Place of Presentation
      神戸国際会議場(兵庫県 神戸市)
    • Year and Date
      2015-10-22
    • Related Report
      2015 Research-status Report
  • [Presentation] 関節超音波を用いた生物学的製剤の治療反応の評価:生物学的製剤のスイッチングの観点から2015

    • Author(s)
      西野文子,川尻真也,川上 純,吉玉珠美,榮樂信隆,松岡直樹,植木幸孝,岡田覚丈,都留智巳,日高利彦,濱田浩朗,藤川敬太,永野修司,有信洋二郎,田中良哉,井田弘明
    • Organizer
      第50回九州リウマチ学会
    • Place of Presentation
      鹿児島県医師会館(鹿児島県 鹿児島市)
    • Year and Date
      2015-09-05
    • Related Report
      2015 Research-status Report
  • [Presentation] 関節リウマチ患者におけるインドシアニングリーン増強蛍光光学画像検査の有用性2015

    • Author(s)
      川尻真也,西野文子,梅田雅孝,福井翔一,中島好一,鈴木貴久,古賀智裕,岩本直樹,一瀬邦弘,玉井慎美,中村英樹,折口智樹,青栁 潔,川上 純
    • Organizer
      第50回九州リウマチ学会
    • Place of Presentation
      鹿児島県医師会館(鹿児島県 鹿児島市)
    • Year and Date
      2015-09-05
    • Related Report
      2015 Research-status Report

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Published: 2015-04-16   Modified: 2020-03-30  

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