抗酸菌で誘導される免疫抑制性マクロファージのサプレッサー機能の発現メカニズム

• 研究課題/領域番号: 10670255
• 研究種目: 基盤研究(C)
• 配分区分: 補助金
• 応募区分: 一般
• 研究分野: 細菌学(含真菌学)
• 研究機関: 島根医科大学
• 研究代表者: 冨岡 治明 島根医科大学, 医学部, 教授 (40034045)
• 研究分担者: 佐藤 勝昌 島根医科大学, 医学部, 助手 (00142331) ; 清水 利朗 島根医科大学, 医学部, 助手 (60284030)
• 研究期間 (年度): 1998 – 2000
• 研究課題ステータス: 完了 (2000年度)
• 配分額: 1,600千円 (直接経費: 1,600千円); 2000年度: 800千円 (直接経費: 800千円); 1999年度: 800千円 (直接経費: 800千円)
• キーワード: 抗酸菌 / M.avium complex / サプレッサーMΦ / B7-1 / PD-1 / CTLA-4 / CD28 / サイトカイン / M avium complex / adhesion molecule / B_<7-1>

研究概要

本研究では,M.avium complex誘導マクロファージ(MAC-MΦ)の標的T細胞との細胞間接着を介するsuppressor活性発現メカニズムについて検討した.その結果,MAC-MΦを固定したり,cytochalasin Bなどの処理細胞膜機能を抑制させると活性発現が著しく低下するこから,MAC-MΦのsuppressor活性発現には細胞膜機能が重要である,MAC-MΦの活性発現や標的T細胞との結合能は抗B7-1抗体によりブロックされること,ならびにMAC-MΦではB7-1発現増強がみられることより,MAC-MΦから標的T細胞へのsuppressorシグナルの伝達にはMΦのB7-1分子が重要である,MAC-MΦからの細胞間接触を介しての抑制性シグナルを受けた標的T細胞ではConA増殖性応答が阻害されるが,PMAとCa^<2+>ionophoreに対する増殖性応答は影響されないことから,MAC-MΦの抑制性シグナルはT細胞のPKC活性化以前のシグナル伝達系にcross talkしていると考えられる,標的T細胞を抗CD28,抗CTLA-4抗体でブロックしてもMAC-MΦのサプレッサー活性は阻害されず,MAC-MΦのB7-1分子に対する標的T細胞の側のレセプターは,CD28やCTLA-4以外の未知の分子である可能性がある,MAC-MΦの抑制性シグナルのT細胞への伝達はMΦのB7-1分子のCTLA-4Igによるブロッキングでは阻害されず,MAC-MΦの抑制性シグナル伝達にかかわるB7-1分子は,新しい型のisoformに属す可能性がある,T細胞のlysate中にB7-1との特異的結合能を有する31kD蛋白が検出されたが,このものはその分子量からみてCTLA-4と並ぶ新たな抑制性シグナルのレセプターとして最近発見されたPD-1に相当するものと考えられる,マウス脾細胞にもPD-1分子の発現が認められたが,ConA刺激に応答してその発現がup-regulateされる,MAC-MΦとの混合培養により抑制性シグナルを受け取った脾T細胞では,ConA刺激に応答してのPKCの活性化と細胞膜へのtranslocationが抑制されることなどが明らかになった.

研究成果

• [文献書誌] Sano Chiaki: "The modulating effects of proinflammatory cytokines interferon-gamma (IFN-g) and tumour necrosis factor-alpha (TNF-a), and immunoregulating cytokines IL-10 and transforming growth factor-beta (TGF-b), on anti-microbial activity of murine peritoneal macrophages against Mycobacterium avium-intracellulare complex."Clinical Experimental Immunology. 115. 435-442 (1999)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Shimizu Tosiaki: "Roles of tumor necrosis facter-α and transforming growth factor-beta in regulating intercellular adhesion molecule-1 expression on murine peritoneal macrophages infected with Mycobacterium leprae."Internationl Journal of Leprosy. 67. 36-45 (1999)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Shimizu Tosiaki: "Effects of Chinese traditional medicine Mao-Bushi-saishin-To on therapeutic efficacy of a new benzoxazinorifamycin, KRM-1648, against Mycobacterium avium infection in mice."Antimicrobial Agents & Chemotherapy. 43. 514-519 (1999)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Sano Chiaki: "Effects of secretory leucocyte protease inhibitor on the production of the anti-inflammatory cytokiens, IL-10 and transforming growth factor-beta (TGF-β), by lipopolysaccharide-stimulated macrophages."Clin Exp Immunol.. 121. 77-85 (2000)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Akaki Tatsuya: "Comparative roles of free fatty acids with reactive nitrogen intermediates and reactive oxygen intermediates in expression of the anti-microbial activity of macrophage against Mycobacterium tuberculosis."Clin Exp Immunol.. 121. 302-310 (2000)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Tomioka Haruaki: "Roles of tumour necrosis factor-alpha (TNF-α), transforming growth factor-beta (TGF-β), and IL-10 in the modulation of intercellular adhesion molecule-1 (ICAM-1) expression by macrophages during mcobacterial infection."Clin Exp Immunol.. 122. 335-342 (2000)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] 冨岡治明: "免疫抑制マクロファージ"臨床免疫. 33. 29-36 (2000)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] 冨岡治明: "らい菌感染宿主に誘導されるサイトカイン産生異常"臨床免疫. 34. 145-152 (2000)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Sato K, Akaki T, Tomioka H: "Differential potentiation of anti-mycobacterial activity and reactive nitrogen intermediate-producing ability of murine peritoneal macrophages activated by interferon-gamma (IFN-γ) and tumour necrosis factor-alpha (TNF-α)."Clin.Exp.Immunol.. 112. 63-68 (1998)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Sano C, Sato K, Shimizu T, Kajitani H, Kawauchi H, Tomioka H: "The modulating effects of proinflammatory cytokines interferon-gamma (IFN-γ) and tumour necrosis factor-alpha (TNF-α), and immunoregulating cytokines IL-10 and transforming growth facotr-beta (TGF-β), on anti-mirobial activity of murine peritoneal macrophages against Mycobacterium avium-intracellulare complex."Clin.Exp.Immunol.. 115. 435-442 (1999)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Shimizu T, Tomioka H, Sato K, Sano C, Akaki T, Dekio S, Yamada Y, Kamei T, Shibata H, Higashi N: "Effects of Chinese traditional medicine Mao-Bushi-Saishin-To on therapeutic efficacy of a new benzoxazinorifamycin, KRM-1648, against Mycobacterium avium infection in mice."Antimicrob.Agents.Chemother.. 43. 514-519 (1999)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Sano C, Shimizu T, Sato K, Kawauchi H, Tomioka H: "Effects of secretory leucocyte protease inhibitor on the production of the anti-inflammatory cytokines, IL-10 and transforming growth factor-beta (TGF-β), by lipopolysaccharide-stimulated macrophages."Clin.Exp.Immunol.. 121. 77-85 (2000)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Tomioka H, Shimizu T, Maw WW, Ogasawara K: "Roles of tumour necrosis factor-alpha (TNF-α), transforming growth factor-beta (TGF-β), and IL-10 in the modulation of intercellular adhesion molecule-1 (ICAM-1) expression by macrophages during mycobacterial infection."Clin.Exp.Immunol.. 122. 335-342 (2000)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Tomioka H: "[Rview] Immunosuppressive macrophages. (in Japanese)"Clin.Immunol.. 33. 29-36 (2000)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Tomioka H: "[Rview] Changes in cytokine profiles induced by the infection with leprosy bacilli. (in Japanese)"Clin.Immunol.. 34. 145-152 (2000)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Tomioka H: "[Rview] Profiles of cytokine network in the hosts with mycobacterial infection.(in Japanese)"Clin.Immunol.. (in press). (2001)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Tomioka Haruaki: "Comparative in vitro antimicrobial activities of the newly synthesized quinolone WQ-3034, levofloxacin, sparfloxacin, and ciprofloxacin against Mycobacterium tuberculosis and Mycobacterium avium complex."Antimicrobial Agents & Chemotherapy. 44. 283-286 (2000)
• [文献書誌] Tomioka Haruaki: "Prospects for development of new antimycobacterial drugs."J Infect Chemother. 6. 8-20 (2000)
• [文献書誌] Sato Katsumasa: "Antimicrobial activities of levofloxacin, clarithromycin, and KRM-1648 against Mycobacterium tuberculosis and Mycobacterium avium complex replicating within Mono Mac 6 human macrophage and A-549 type II alveolar cell lines."Int J Antimicrob Agents. 16. 25-29 (2000)
• [文献書誌] Sano Chiaki: "Effects of secretory leucocyte protease inhibitor on the production of the antiinflammatory cytokiens, IL-10 and transforming growth factor-beta(TGF-β), by lipopolysaccharide-stimulated macrophages."Clin Exp Immunol.. 121. 77-85 (2000)
• [文献書誌] Akaki Tatsuya: "Comparative roles of free fatty acids with reactive nitrogen intermediates and reactive oxygen intermediates in expression of the anti-microbial activity of macrophage against Mycobacterium tuberculosis."Clin Exp Immunol.. 121. 302-310 (2000)
• [文献書誌] Tomioka Haruaki: "Roles of tumour necrosis factor-alpha (TNF-α), transforming growth factorbeta(TGF-β), and IL-10 in the modulation of intercellular adhesion molecule-1(ICAM-1) expression by macrophages during mycobacterial infection."Clin Exp Immunol.. 122. 335-342 (2000)
• [文献書誌] 冨岡治明: "免疫抑制マクロファージ"臨床免疫. 33. 29-36 (2000)
• [文献書誌] 冨岡治明: "らい菌感染宿主に誘導されるサイトカイン産生異常"臨床免疫. 34. 145-152 (2000)
• [文献書誌] Sano Chiaki: "The modulating effects of proinflammatory cytokines interferon-gamma (IFN-γ) and tumour necrosis factor-alpha (TNF-α),and immunoregulating cytokines IL-10 and transforming growth factor-beta (TGF-β),on anti-microbial activity of murine peritoneal macrophages against Mycobacterium avium-intracellulare complex"Clinical Experimental Immunonlogy. 115. 435-442 (1999)
• [文献書誌] Shimizu Toshiaki: "Roles of tumor necrosis facter-α and transforming growth factor-beta in regulating intercellular adhesion molecule-1 expression on murine peritoneal macrophages infected with Mycobacterium Leprae."Internationl Journal of Leprosy. 67. 36-45 (1999)
• [文献書誌] Shimizu Toshiaki: "Effects of Chinese traditional medicine Mao-Bushi-saishin-To on therapeutic efficacy of a new benzoxazinorifamycin, KRM-1648, against Mycobacterium avium infection in mice."Antimicrobial Agents & Chemotherapy. 43. 514-519 (1999)
• [文献書誌] Tomioka Haruaki: "Comparative in vitro antimicrobial activities of the newly synthesized quinolone HSR-903, sitafloxacin(DU-6859a),gatifloxacin(AM-1155),and levofloxacin against Mycobacterium tuberculosis and Mycobacterium avium complex."Antimicrobial Agents & Chemotherapy. 43. 3001-3004 (1999)
• [文献書誌] Tomioka Haruaki: "Comparative in vitro antimicrobial activities of the newly synthesized quinolone WQ-3034,levofloxacin,sparfloxacin,and ciprofloxacin against Mycobacterium tuberculosis and Mycobacterium avium complex."Antimicrobial Agents & Chemotherapy. 44. 284-286 (2000)
• [文献書誌] Tomioka Haruaki: "Prospects for development of new antimycobacterial drugs."Journal of Infection and Chemotherapy. 6. 8-20 (2000)
• [文献書誌] 冨岡治明: "免疫抑制マクロファージ"臨床免疫. 33. 29-36 (2000)
• [文献書誌] 冨岡治明: "らい菌感染宿主に誘導されるサイトカイン産生異常"臨床免疫. 33. (2000)
• [文献書誌] Sato Katumasa: "Differential potentiation of anti-mycobacterial activity and reactive nitrogen intermediate-producing ability of murin peritoneal macrophages activated by interferon-gamma and tumor necrosis facter-alpa." Clinical Experimental Immunology. 112. 63-68 (1998)
• [文献書誌] Sano Chiaki: "The modulating effects of proinflammatory cytokines interferon-gamma (IFN-γ) and tumour necrosis factor-alpha (TNF-α), and immunoregulating cytokines IL-10 and transforming growth factor-beta (TGF-β), on anti-microbial activity of murine peritoneal macrophages against Mycobacterium avium-intracellulare complex." Clinical Experimental Immunology. (1999)
• [文献書誌] Shimizu Tosiaki: "Roles of tumor necrosis facter-α transforming growth factor-beta in regulating intercellular adehesion molecule-1 expression on murin peritoneal macrophages infected with Mycobacterium leprae." Intenationl Journal of Leprosy. (1999)
• [文献書誌] Sano Chiaki: "Therapeutic effects of benzoxazinorifamycin KRM-1648 administered alone or in combination with a half-sized secretory leukocyte protease inhibitor or the nonsteroidal anti-inflammatory drug diclofenac.sodium against Mycobacterium avium complex infection in mice" Antimicrobial Agents & Chemotherapy. 43. 360-364 (1999)
• [文献書誌] Shimizu Tosiaki: "Effects of Chinese traditional medicine Mao-Bushi-saishin-To on therapeutic efficacy of a new benzoxazinorifamycin,KRM-1648,against Mycobacterium avium infection in mice." Antimicrobial Agents & Chemotherapy. (1999)
• [文献書誌] Sato Katumasa: "Antimicrobial activities of benzoxazinorifamycin (KRM-1648) and clarithromycin against Mycobacterium avium-intracellulare complex residing in murine peritoneal macrophages,human macrophage-like cells and human alveolar epithelial cells." Journal of Antimicrobial Chemotherapy. (1999)
• [文献書誌] 冨岡 治明: "微生物学 免疫学 (6.抗酸菌, 7.放線菌とノカルジア)" 医学教育出版社, 129-143 (1998)