Basic research for searching of new therapeutic targets of rheumatoid arthritis through investigation of novel action of CTLA-4-Ig
Project/Area Number |
15K09531
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Research Field |
Collagenous pathology/Allergology
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Research Institution | Nagasaki University |
Principal Investigator |
KAWAKAMI Atsushi 長崎大学, 医歯薬学総合研究科(医学系), 教授 (90325639)
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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)
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Project Period (FY) |
2015-04-01 – 2019-03-31
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Project Status |
Completed (Fiscal Year 2018)
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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)
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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.
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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。
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Report
(5 results)
Research Products
(28 results)
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[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
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Journal Title
Rheumatology
Volume: 57
Issue: 4
Pages: 718-726
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[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
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Journal Title
Mod Rheumatol
Volume: 印刷中
Issue: 6
Pages: 1-6
DOI
Related Report
Peer Reviewed
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[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.
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Journal Title
Arthritis Res Ther
Volume: 13
Issue: 1
Pages: 293-293
DOI
NAID
Related Report
Peer Reviewed / Open Access
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[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
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Journal Title
Journal of Rheumatology
Volume: 43
Issue: 7
Pages: 7-13
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[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.
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Journal Title
Journal of Rheumatology
Volume: 42
Issue: 6
Pages: 943-947
DOI
Related Report
Peer Reviewed
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[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
Int'l Joint Research
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[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
Int'l Joint Research
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[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
Int'l Joint Research
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[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
Int'l Joint Research
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[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
Int'l Joint Research
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[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
Int'l Joint Research
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[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
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[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
Int'l Joint Research
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[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
Int'l Joint Research
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