CCL18-CCR8 axis and novel disease specific therapeutic targets for IgG4-related disease

• Project/Area Number: 15K09519
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Collagenous pathology/Allergology
• Research Institution: University of Tsukuba
• Principal Investigator: Tsuboi Hiroto 筑波大学, 医学医療系, 講師 (80580505)
• 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: IgG4関連疾患 / シェーグレン症候群 / ケモカイン / CCL18 / CCR8 / 口唇唾液腺 / 涙腺

Outline of Final Research Achievements

We clarified that CCL18 expressing macrophages, dendritic cells, and plasmacytes were significantly increased in labial salivary glands (LSGs) of IgG4-related disease (IgG4-RD) compared with Sjögren’s syndrome (SS) and healthy controls (HC). In LSGs of IgG4-RD and SS, T, B cells and plasmacytes expressed CCR8 which is a receptor for CCL18, whereas not in LSGs of HC. Peripheral blood mononuclear cells (PBMCs) and peripheral B cells stimulated with CD40L, IL-4, IL-10, and IL-21 significantly highly produced IgG4 compared with those stimulated with CD40L and IL-4. Moreover addition of CCL18 enhanced IgG4 production from PBMCs and peripheral B cells stimulated with CD40L, IL-4, IL-10, and IL-21. These findings suggested that the CCL18-CCR8 axis might be a novel therapeutic target for IgG4-RD.

Research Products

• [Journal Article] IgG4関連疾患の病因-分子生物学的アプローチ (2017)
  • Author(s): 坪井洋人、飯塚麻菜、高橋広行、浅島弘充、廣田智哉、近藤裕也、中井雄治、阿部啓子、田中昭彦、森山雅文、中村誠司、吉原俊雄、松本功、住田孝之
  • Journal Title: 日本臨床リウマチ学会雑誌 Volume: 29 Pages: 128-139
  • NAID: 130006068221
  • Peer Reviewed
• [Journal Article] Interleukin-33 produced by M2 macrophages and other immune cells contributes to Th2 immune reaction of IgG4-related disease (2017)
  • Author(s): Furukawa S, Moriyama N, Miyake K, Nakashima H, Tanaka A, Maehara T, Iizuka-Koga M, Tsuboi H, Hayashida JN, Ishiguro N, Yamauchi M, Sumida T, Nakamura S
  • Journal Title: Scientific Reports Volume: 7 Pages: 42413-42413
  • NAID: 120007135019
  • Peer Reviewed
• [Journal Article] A multicenter phase II prospective clinical trial of glucocorticoid for patients with untreated IgG4-related disease (2017)
  • Author(s): Masaki Y, Matsui S, Saeki T, Tsuboi H, et al
  • Journal Title: Modern Rheumatology Volume: 27 Pages: 849-854
• [Presentation] IgG4関連疾患の病因・病態の解明：シェーグレン症候群との比較から見えてきたもの (2017)
  • Author(s): 坪井洋人、飯塚麻菜、高橋広行、浅島弘充、工藤華枝、小野由湖、安部沙織、近藤裕也、中井雄治、阿部啓子、田中昭彦、森山雅文、中村誠司、松本功、住田孝之
  • Organizer: 2017年第4回日本リウマチ学会、ベーシックリサーチカンファレンス
  • Invited
• [Presentation] IgG4関連疾患の病変局所におけるCCL18-CCR8シグナルの発現亢進 (2016)
  • Author(s): 坪井洋人、飯塚麻菜、浅島弘充、高橋広行、廣田智哉、近藤裕也、松本功、住田孝之
  • Organizer: 第60回日本リウマチ学会総会・学術集会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
• [Presentation] IgG4関連疾患 vs シェーグレン症候群：遺伝子発現比較からみた病因・病態の違い (2016)
  • Author(s): 坪井洋人、高橋広行、飯塚麻菜、浅島弘充、廣田智哉、近藤裕也、中井雄治、阿部啓子、田中昭彦、森山雅文、中村誠司、吉原俊雄、松本功、住田孝之
  • Organizer: 第25回日本シェーグレン症候群学会学術集会
  • Place of Presentation: 京王プラザホテル（東京都新宿区）
• [Presentation] IgG4関連疾患の病因-分子生物学的アプローチ- (2016)
  • Author(s): 坪井洋人、飯塚麻菜、高橋広行、浅島弘充、廣田智哉、近藤裕也、中井雄治、阿部啓子、田中昭彦、森山雅文、中村誠司、吉原俊雄、松本功、住田孝之
  • Organizer: 第31回日本臨床リウマチ学会
  • Place of Presentation: 京王プラザホテル（東京都新宿区）
• [Presentation] Up-regulation of CCL18-CCR8 signaling in affected tissues of patients with IgG4-related disease (2015)
  • Author(s): Tsuboi H, Iizuka M, Asashima H, Takahashi H, Hirota T, Kondo Y, Matsumoto I, Sumida T
  • Organizer: 第44回日本免疫学会総会・学術集会
  • Place of Presentation: 札幌コンベンションセンター
  • Year and Date: 2015-11-19
• [Presentation] Up-regulation of CCL18-CCR8 signaling in patients with IgG4-related disease (2015)
  • Author(s): Tsuboi H, Iizuka M, Asashima H, Takahashi H, Hirota T, Kondo Y, Matsumoto I, Sumida T
  • Organizer: 第59回日本リウマチ学会総会・学術集会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2015-04-24
• [Book] IgG4関連疾患 実践的臨床から病因へ IgG4研究会モノグラフ ケモカインとIgG4関連疾患 (2015)
  • Author(s): 坪井洋人、中井雄治、飯塚麻菜、森山雅文、吉原俊雄、中村誠司、阿部啓子、住田孝之
  • Total Pages: 206
  • Publisher: 前田書店