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

2018 Fiscal Year Final Research Report

• Project/Area Number: 15K09531
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Collagenous pathology/Allergology
• 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)
• 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
• 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

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.

Free Research Field

リウマチ・膠原病学

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。