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STUDIES ON THE MECHANISMS FOR EXPRESSION OF THE SUPPRESSOR ACTIVITY BY MYCOBACTERIUM AVIUM COMPLEX-INDUCED IMMUNOSUPPRESSIVE MACROPHAGES

Research Project

Project/Area Number 10670255
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Bacteriology (including Mycology)
Research InstitutionSHIMANE MEDIACL UNIVERSITY

Principal Investigator

TOMIOKA Haruaki  SHIMANE MEDIACL UNIVERSITY, PROFESSOR, 医学部, 教授 (40034045)

Co-Investigator(Kenkyū-buntansha) SATO Katsumasa  SHIMANE MEDIACL UNIVERSITY, ASSISTANT, 医学部, 助手 (00142331)
SHIMIZU Toshiaki  SHIMANE MEDIACL UNIVERSITY, ASSISTANT, 医学部, 助手 (60284030)
Project Period (FY) 1998 – 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2000: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1999: ¥800,000 (Direct Cost: ¥800,000)
KeywordsMycobacteria / M.avium complex / Suppressor MΦ / B7-1 / PD-1 / CTLA-4 / CD28 / Cytokine / M avium complex / adhesion molecule / B_<7-1>
Research Abstract

We studied profiles of cell-to-cell interaction of immunosuppressive macrophages (MΦs) induced by Mycobacterium avium complex infection (MAC-MΦs) with target T cells. First, experiments using a dual chamber system indicated that cell contact is required for full expression of the MΦ suppressor activity against concanavalin A (Con A)-induced T cell mitogenesis. MAC-MΦs displayed suppressor activity in an H-2 allele-independent manner, indicating that MHC molecules are not required for such cell contact. The suppressor activity of MAC-MΦs was markedly reduced by treatment with either paraformaldehyde, cytochalasin B, or colchicine, indicating that vital membrane functions of MAC-MΦs are required for the expression of suppressor activity. Second, blocking experiments using antibodies (Abs) against adhesion molecules indicated that B7-1 but none of B7-2, ICAM-1, or VCAM-1 molecules were required for expression of the MΦ suppressor activity. Indeed, MAC-MΦs displayed markedly increased B7-1 … More expression in parallel with the acquisition of the suppressor activity. Third, Ab-blocking of CD28 and CTLA-4 on target T cells did not reduce the suppressor activity of MAC-MΦs. Thus, there may exist another type of surface molecules on target T cells, that serves as a receptor for B7-1-mediated suppressive signals from MAC-MΦs. Fourth, precultivation of splenocytes (SPCs) with MAC-MΦs reduced Con A-induced mitogenesis but not phorbol myristate acetate (PMA)/Ca^<2+> ionophore A23187-elicited proliferation of the SPCs. Thus, when resting T cells receive suppressive signals from MAC-MΦs via cell contact and are subsequently subjected to a Con A stimulatory signal, MΦ-derived suppressor signals may interfere with the upstream events of protein kinase C(PKC) activation or intracellular Ca^<2+> mobilization. Indeed, Co-cultivation of splenic T cells with MAC-MΦs reduced Con A-induced PKC activation and its translocation to the cell membrane in the T cells. Fifth, when MAC-MΦs came in contact with T cells which had been subjected to PMA/A23187 signals, T cell proliferative response was strongly suppressed. Thus, when PMA/A23187-induced signal transduction events have already been mobilized in target T cells, MAC-MΦ suppressor signals can also cross-talk with the downstream pathways of PKC activation or Ca^<2+> mobilization. Less

Report

(4 results)
  • 2000 Annual Research Report   Final Research Report Summary
  • 1999 Annual Research Report
  • 1998 Annual Research Report
  • Research Products

    (39 results)

All Other

All Publications (39 results)

  • [Publications] 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)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] 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)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] 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)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] 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)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] 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)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] 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)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] 冨岡治明: "免疫抑制マクロファージ"臨床免疫. 33. 29-36 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] 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)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] 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)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] 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)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] 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)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] 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)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] 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)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Tomioka H: "[Rview] Immunosuppressive macrophages. (in Japanese)"Clin.Immunol.. 33. 29-36 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Tomioka H: "[Rview] Changes in cytokine profiles induced by the infection with leprosy bacilli. (in Japanese)"Clin.Immunol.. 34. 145-152 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Tomioka H: "[Rview] Profiles of cytokine network in the hosts with mycobacterial infection.(in Japanese)"Clin.Immunol.. (in press). (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] 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)

    • Related Report
      2000 Annual Research Report
  • [Publications] Tomioka Haruaki: "Prospects for development of new antimycobacterial drugs."J Infect Chemother. 6. 8-20 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 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)

    • Related Report
      2000 Annual Research Report
  • [Publications] 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)

    • Related Report
      2000 Annual Research Report
  • [Publications] 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)

    • Related Report
      2000 Annual Research Report
  • [Publications] 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)

    • Related Report
      2000 Annual Research Report
  • [Publications] 冨岡治明: "免疫抑制マクロファージ"臨床免疫. 33. 29-36 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 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)

    • Related Report
      2000 Annual Research Report
  • [Publications] 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)

    • Related Report
      1999 Annual Research Report
  • [Publications] 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)

    • Related Report
      1999 Annual Research Report
  • [Publications] 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)

    • Related Report
      1999 Annual Research Report
  • [Publications] 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)

    • Related Report
      1999 Annual Research Report
  • [Publications] 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)

    • Related Report
      1999 Annual Research Report
  • [Publications] Tomioka Haruaki: "Prospects for development of new antimycobacterial drugs."Journal of Infection and Chemotherapy. 6. 8-20 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] 冨岡治明: "免疫抑制マクロファージ"臨床免疫. 33. 29-36 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] 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)

    • Related Report
      1999 Annual Research Report
  • [Publications] 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)

    • Related Report
      1998 Annual Research Report
  • [Publications] 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)

    • Related Report
      1998 Annual Research Report
  • [Publications] 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)

    • Related Report
      1998 Annual Research Report
  • [Publications] 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)

    • Related Report
      1998 Annual Research Report
  • [Publications] 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)

    • Related Report
      1998 Annual Research Report
  • [Publications] 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)

    • Related Report
      1998 Annual Research Report
  • [Publications] 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)

    • Related Report
      1998 Annual Research Report

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Published: 1999-04-01   Modified: 2016-04-21  

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