Study on the pathophysiological role of the Th2-type chemokine receptor CCR4

• Project/Area Number: 19390277
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: 膠原病・アレルギー・感染症内科学
• Research Institution: Kinki University
• Principal Investigator: YOSHIE Osamu Kinki University, 医学部, 教授 (10166910)
• Co-Investigator(Kenkyū-buntansha): HIESHIMA Kunio 近畿大学, 医学部, 准教授 (10322570) ; NAKAYAMA Takashi 近畿大学, 医学部, 講師 (60319663) ; NAGAKUDO Daisuke 近畿大学, 医学部, 助教 (10368293) ; SHIRAKAWA Aiko 近畿大学, 医学部, 助教 (30260285)
• Project Period (FY): 2007 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥18,070,000 (Direct Cost: ¥13,900,000、Indirect Cost: ¥4,170,000); Fiscal Year 2009: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2008: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2007: ¥7,800,000 (Direct Cost: ¥6,000,000、Indirect Cost: ¥1,800,000)
• Keywords: CCR4 / CCL17 / CCL22 / Th2 / Treg / アレルギー / 喘息 / アトピー / TARC / MDC / 制御性T細胞 / ブレオマイシン誘導肺線維症 / ケモカイン / ケモカイン受容体 / 胸腺 / T細胞分化

Research Abstract

CCR4 is a chemokine receptor selectively expressed by Th2 cells, regulatory T cells, and skin-homing T cells. We have shown a potent ther apeutic effect of a small molecule CCR4 inhibitor on Th2-induced airway inflammation in mice. We have also shown that CCR4 and its ligand MDC/CCL22 mediate immunosuppressive interactions of dendritic cells and regulatory T cells in mesenteric lymphonodes. Furthermore, human oncogenic viruses such as EBV and HTLV-1 commonly induce expression of MDC/CCL22 in infected host cells to attract Th2 cells and regulatory T cells for immunoevasion and virus propagation.

Research Products

• [Journal Article] Tumor-infiltrating lymphocytes, particularly the balance between CD8+ T cells and CCR4+ regulatory T cells, affect the survival of patients with ortal squamous cell carcinoma. (2010)
  • Author(s): Watanebe Y, Katou F, Ohtani H, Nakayma T, Yoshie O, Hashimoto K
  • Journal Title: Oral Surgary, Oral Medicine, Oral Pathology, Oral Radiology, and Endocrionology
  • Peer Reviewed
• [Journal Article] Constitutive expression of IDO by dendritic cells of mesenteric lymph nodes: Functional involvement of the CTLA-4/B7 and CCL22/CCR4 interactions. (2009)
  • Author(s): Onodera T, Jang MH, Guo Z, Yamasaki M, Hirata T, Bai Z, Tsuji NM, Nagakubo D, Yoshie O, Sakaguchi S, Takikawa O, Miyasaka M
  • Journal Title: J. Immunol 183 Pages: 5608-5614
  • Peer Reviewed
• [Journal Article] Abundant expression of CXCL9 (MIG) by stromal cells that include dendritic cells and accumulation of CXCR3+ T cells in lymphocyte-rich gastric carcinoma. (2009)
  • Author(s): Ohtani H, Jin Z, Takegawa S, Nakayama T, Yoshie O
  • Journal Title: J. Pathol 217 Pages: 21-31
  • Peer Reviewed
• [Journal Article] Constitutive expression of IDO by dendritic cells of mesenteric lymph nodes : functional involvement of the CTLA-4/B7 and CCL22/CCR4 interactions (2009)
  • Author(s): Toshiharu ONODERA
  • Journal Title: Journal of Immunology 183 Pages: 5608-5614
  • Peer Reviewed
• [Journal Article] Differential regulatory function of resting and preactivated allergen-specific CD4+CD25+ regulatory T cells in Th2-type airway inflammation. (2008)
  • Author(s): Saito K, Torii M, Ma N, Tsuchiya T, Wang L, Hori T, Nagakubo D, Nitta N, Kanegasaki S, Hieshima K, Yoshie O, Gabazza EC, Katayama N, Shiku H, Kuribayashi K, Kato T
  • Journal Title: J. Immunol 181 Pages: 6889-6897
  • Peer Reviewed
• [Journal Article] NF-κB-mediated activation of the chemokine CCL22 by the product of the human cytomegalovirus gene UL144 escapes regulation by viral IE86. (2008)
  • Author(s): Poole E, Atkins E, Nakayama T, Yoshie O, Groves I, Alcami A, Sinclair J
  • Journal Title: J. Virol 82 Pages: 4250-4256
  • Peer Reviewed
• [Journal Article] Expression of CCL17 and CCL22 by latent membrane protein 1-positive tumor cells in age-related Epstein-Barr virus-associated B-cell lymphoproliferative disorder. (2008)
  • Author(s): Takegawa S, Jin Z, Nakayama T, Oyama T, Hieshima K, Nagakubo D, Shirakawa AK, Tsuzuki T, Nakamura S, Yoshie O
  • Journal Title: Cancer Sci 99 Pages: 296-302
  • NAID: 10024002305
  • Peer Reviewed
• [Journal Article] Tax-inducible production of CC chemokine ligand 22 by human T cell leukemia virus type 1 (HTLV-1)-infected T cells promotes preferential transmission of HTLV-1 to CCR4-expressing CD4+ T cells. (2008)
  • Author(s): Hieshima K, Nagakubo D, Nakayama T, Shirakawa AK, Jin Z, Yoshie O
  • Journal Title: J. Immunol 180 Pages: 931-939
  • Peer Reviewed
• [Journal Article] Aberrant expression of Fra-2 promotes CCR4 expression and cell proliferation in adult T-cell leukemia (2008)
  • Author(s): Nakayama T
  • Journal Title: Oncogene 27(23) Pages: 3221-3232
  • Peer Reviewed
• [Journal Article] NF-kB-mediated activation of the chemokine CCL22 by the product of the human cytomegalovirus gene UL144 escapes regulation by viral IE86 (2008)
  • Author(s): Poole E
  • Journal Title: Journal of Virology 82(9) Pages: 4250-4256
  • Peer Reviewed
• [Journal Article] Differential regulatory function of resting and preactivated allergen-specific CD4+CD25+ regulatory T cells in Th2-type airway inflammation (2008)
  • Author(s): Saito K
  • Journal Title: Journal of Immunology 181(10) Pages: 6889-6897
  • Peer Reviewed
• [Journal Article] Selective suppression of Th2-mediated airway eosinophil infiltration by low-molecular weight CCR3 antagomsts (2007)
  • Author(s): Mori A
  • Journal Title: International Immunology 19 Pages: 913-921
  • Peer Reviewed
• [Presentation] T細胞依存性の好酸球性気道炎症に対するCCR4拮抗薬の作用 (2009)
  • Author(s): 神沼修
  • Organizer: アレルギー学会
  • Place of Presentation: 秋田市
  • Year and Date: 2009-10-29
• [Presentation] T細胞依存性の好酸球性気道炎症に対するCCR4拮抗薬の作用 (2008)
  • Author(s): 神沼修、大友隆之、森晶夫、長久保大輔、稗島州雄、義江修、鈴木一矢、廣井隆親
  • Organizer: 第59回日本アレルギー学会秋季学術大会
  • Place of Presentation: 秋田
• [Presentation] 加齢関連EBV+B細胞リンパ増殖症における多様なケモカインの発現 (2008)
  • Author(s): 義江修、竹川澄男、中山隆志、白川愛子、樋口智紀、長久保大輔、重田暁子、稗島州雄、中村栄男
  • Organizer: 第67回日本癌学会総会
  • Place of Presentation: 名古屋
• [Presentation] CCR4を発現するATLとCTCLにおけるFra-2の異常発現 (2008)
  • Author(s): 中山隆志、樋口智紀、竹川澄男、長久保大輔、重田暁子、白川愛子、稗島州雄、義江修
  • Organizer: 第67回日本癌学会総会
  • Place of Presentation: 名古屋
• [Presentation] ケモカイン受容体CCR4とHTLV-1感染、ATL発がん (2008)
  • Author(s): 義江修
  • Organizer: 第29回日本炎症・再生医学会
  • Place of Presentation: 東京
• [Presentation] O. Role of Fra-2/JunD heterodimer in CCR4 expression and cell proliferation in adult T-cell leukemia. (2007)
  • Author(s): Nakayama, T., Hieshima, K., Jin, Z., Nagakubo, D., Shirakawa, A., Yoshie, O
  • Organizer: 第37回日本免疫学会総会・学術集会
  • Place of Presentation: 東京
• [Presentation] HTLV-1のCD4+ T細胞への感染におけるケモカイン/ケモカイン受容体CCL22/CCR4の役割 (2007)
  • Author(s): 稗島州雄、中山隆志、白川愛子、義江修
  • Organizer: 第55回日本ウイルス学会学術集会
  • Place of Presentation: 札幌
• [Presentation] Fra-2とJunDのヘテロダイマーはATL細胞におけるCCR4発現と細胞増殖を促進する (2007)
  • Author(s): 中山隆志、稗島州雄、金哲、長久保大輔、白川愛子、山田恭暉、藤井雅寛、義江修
  • Organizer: 第66回日本癌学会総会
  • Place of Presentation: 横浜
• [Presentation] HTLV-1 Tax誘導性ケモカインCCL22のHTLV-1初期感染における役割 (2007)
  • Author(s): 稗島州雄、中山隆志、長久保大輔、白川愛子、金哲、義江修
  • Organizer: 第66回日本癌学会総会
  • Place of Presentation: 横浜
• [Remarks]
  • URL: http://www.med.kindai.ac.jp/microbio/