Investigation of the role of CD226+CD8+T cells in the pathogenesis of systemic sclerosis and an application to therapy

• Project/Area Number: 15K09527
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Collagenous pathology/Allergology
• Research Institution: Kyushu University
• Principal Investigator: Tsukamoto Hiroshi 九州大学, 医学研究院, 共同研究員 (70304772)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: CD226 / 全身性強皮症 / サイトカイン / 細胞傷害活性 / CD8陽性T細胞 / IL-13 / 細胞障害活性 / グランザイム / 共刺激分子

Outline of Final Research Achievements

CD226highCD8+ T cells were increased in SSc patients compared with healthy controls and were appreciably associated with the severity of skin sclerosis and interstitial lung disease. Further, CD226highCD8+ T cells from SSc patients showed upregulated cytokine production including IL-13 and positive correlation with the cytotoxic capacity of CD8+ T cells against HUVECs. Finally, the neutralization of CD226 in CD8+ T cells impaired co-stimulation, cytokine productions, and cytolysis against HUVECs. These findings indicate that upregulated CD226 expression on CD8+ T cells reflects disease severity and are involved in SSc pathogenesis via the production of various cytokines including profibrotic IL-13 and endothelial cell injury, and that CD226 may be a useful target in the treatment of SSc.

Research Products

• [Journal Article] Shared epitope positivity is related to efficacy of abatacept in rheumatoid arthritis. (2018)
  • Author(s): Oryoji K, Yoshida K, Kashiwado Y, Tanaka K, Mizuki SI, Tsukamoto H, Kamada K, Akashi K.
  • Journal Title: Ann Rheum Dis Volume: 印刷中 Pages: annrheumdis-2017-211430
  • DOI: 10.1136/annrheumdis-2017-211430
  • Peer Reviewed
• [Journal Article] Beneficial use of serum ferritin and heme oxygenase-1 as biomarkers in adult-onset Still's disease: A multicenter retrospective study. (2018)
  • Author(s): Kirino Y, Kawaguchi Y, Tada Y, Tsukamoto H, Ota T, Iwamoto M, Takahashi H, Nagasawa K, Takei S, Horiuchi T, Ichida H, Minota S, Ueda A, Ohta A, Ishigatsubo Y.
  • Journal Title: Mod Rheumatol Volume: 印刷中 Issue: 5 Pages: 1-7
  • DOI: 10.1080/14397595.2017.1422231
  • Peer Reviewed
• [Journal Article] A novel scoring system based on common laboratory tests predicts the efficacy of TNF-inhibitor and IL-6 targeted therapy in patients with rheumatoid arthritis: a retrospective, multicenter observational study. (2017)
  • Author(s): Nakagawa J, Koyama Y, Kawakami A, Ueki Y, Tsukamoto H, Horiuchi T, Nagano S, Uchino A, Ota T, Akahoshi M, Akashi K.
  • Journal Title: Arthritis Res Ther Volume: 19 Issue: 1
  • DOI: 10.1186/s13075-017-1387-9
  • Peer Reviewed / Open Access
• [Journal Article] Smoking history, alcohol consumption, sports activity and the risk of developing systemic lupus erythematosus in a Japanese population. (2017)
  • Author(s): Nakano TW, M., Kiyohara, C,; Tsukamoto,H.; Sawabe, T.; Nishizaka, H.; Horiuchi, T .
  • Journal Title: Int Med J Volume: 24 Pages: 366-70
  • Peer Reviewed
• [Journal Article] Functional interleukin-33 receptors are expressed in early progenitor stages of allergy-related granulocytes. (2017)
  • Author(s): Tsuzuki H, Arinobu Y, Miyawaki K, Takaki A, Ota SI, Ota Y, Mitoma H, Akahoshi M, Mori Y, Iwasaki H, Niiro H, Tsukamoto H, and Akashi K.
  • Journal Title: Immunology Volume: 150 Issue: 1 Pages: 64-73
  • DOI: 10.1111/imm.12667
  • Peer Reviewed / Open Access
• [Journal Article] Clinical and Genetic Features of Patients With TNFRSF1A Variants in Japan: Findings of a Nationwide Survey (2016)
  • Author(s): Ueda, N. Ida, H. Washio, M. Miyahara, H. Tokunaga, S. Tanaka, F. Takahashi, H. Kusuhara, K. Ohmura, K. Nakayama, M. Ohara, O. Nishikomori, R. Minota, S. Takei, S. Fujii, T. Ishigatsubo, Y. Tsukamoto, H. Tahira, T. Horiuchi, T.
  • Journal Title: Arthritis Rheumatol Volume: 68 Issue: 11 Pages: 2760-2771
  • DOI: 10.1002/art.39793
  • Peer Reviewed / Open Access
• [Journal Article] Generation mechanism of RANKL(+) effector memory B cells: relevance to the pathogenesis of rheumatoid arthritis. (2016)
  • Author(s): Ota Y, Niiro H, Ota S, Ueki N, Tsuzuki H, Nakayama T, Mishima K, Higashioka K, Jabbarzadeh-Tabrizi S, Mitoma H, Akahoshi M, Arinobu Y, Kukita A, Yamada H, Tsukamoto H, and Akashi K.
  • Journal Title: Arthritis Res Ther Volume: 18 Issue: 1 Pages: 67-67
  • DOI: 10.1186/s13075-016-0957-6
  • Peer Reviewed / Open Access
• [Journal Article] Quality of life in Japanese female patients with systemic lupus erythematosus: Evaluation using the Short Form 36 Health Survey. (2016)
  • Author(s): Furukawa M, Kiyohara C, Horiuchi T, Tsukamoto H, Mitoma H, Kimoto Y, Uchino A, Nakagawa M, Oryoji K, Shimoda T, and Akashi K.
  • Journal Title: Mod Rheumatol Volume: 26 Issue: 2 Pages: 240-247
  • DOI: 10.3109/14397595.2015.1060668
  • Peer Reviewed
• [Journal Article] Serum progranulin levels are elevated in dermatomyositis patients with acute interstitial lung disease, predicting prognosis. (2015)
  • Author(s): Tanaka A, Tsukamoto H, Mitoma H, Kiyohara C, Ueda N, Ayano M, Ohta S, Kimoto Y, Akahoshi M, Arinobu Y, Niiro H, Tada Y, Horiuchi T and Akashi K.
  • Journal Title: Arthritis research & therapy Volume: 17 Issue: 1 Pages: 27-27
  • DOI: 10.1186/s13075-015-0547-z
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Increased CD226 Expression on CD8+ T Cells Is Associated with Upregulated Cytokine Production and Endothelial Cell Injury in Patients with Systemic Sclerosis. (2015)
  • Author(s): Ayano M, Tsukamoto H, Kohno K, et al.
  • Journal Title: J Immunol Volume: 195 Issue: 3 Pages: 892-900
  • DOI: 10.4049/jimmunol.1403046
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] 関節リウマチ患者のリンパ球サブセットに対するアバタセプトの経時的作用 (2017)
  • Author(s): 三嶋 耕司, 大田 俊一郎, 井上 靖, 吉澤 誠司, 吉澤 滋, 永野 修司, 西坂 浩明, 澤部 琢哉, 押領司 健介, 多田 芳史, 小山 芳伸, 綾野 雅宏, 木本 泰孝, 三苫 弘喜, 赤星 光輝, 有信 洋二郎, 大塚 毅, 上田 章, 大田 俊行, 中島 衡, 塚本 浩, 赤司 浩一, 堀内 孝彦, 新納 宏昭
  • Organizer: 第61回日本リウマチ学会総会・学術集会
• [Presentation] リウマチ性疾患の動物モデル コラーゲン誘導関節炎モデルマウスにおける自然リンパ球の分化と機能に関する検討 (2017)
  • Author(s): Author：高木 綾子, 有信 洋二郎, 大塚 恭子, 入野 健佑, 押領司 大助, 大田 友里, 久本 仁美, 綾野 雅宏, 木本 泰孝, 三苫 弘喜, 赤星 光輝, 塚本 浩, 赤司 浩一, 堀内 孝彦, 新納 宏昭
  • Organizer: 第61回日本リウマチ学会総会・学術集会
• [Presentation] 関節リウマチの治療 病理・病態・バイオマーカー 一般血液検査値による関節リウマチに対する生物製剤治療効果予測の可能性 (2017)
  • Author(s): 中川 仁, 小山 芳伸, 川上 純, 植木 幸孝, 塚本 浩, 永野 修司, 内野 愛弓, 大田 俊行, 赤星 光輝, 綾野 雅宏, 三苫 弘喜, 木本 泰孝, 有信 洋二郎, 赤司 浩一, 堀内 孝彦, 新納 宏昭
  • Organizer: 第61回日本リウマチ学会総会・学術集会
• [Presentation] 膠原病・リウマチ治療の最近の進歩 (2016)
  • Author(s): 塚本 浩
  • Organizer: 第65回共済医学会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-19
• [Presentation] 膠原病の難治性病態 びまん皮膚硬化型全身性強皮症に対する造血幹細胞移植療法の理論的根拠と実際. (2016)
  • Author(s): 塚本 浩
  • Organizer: 第60回日本リウマチ学会総会・学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2016-04-21
• [Presentation] 難治性皮膚筋炎に対する自己造血幹細胞移植の長期成績 (2015)
  • Author(s): 塚本 浩、綾野雅宏、新納宏昭、有信洋二郎、赤星光輝、三苫弘喜、田中 淳、大田俊一郎、植木尚子、久本仁美、上田 彰、廣崎友里、押領司大助、赤司浩一
  • Organizer: 第59回日本リウマチ学会
  • Place of Presentation: 名古屋市
  • Year and Date: 2015-04-23