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IMPROVEMENT OF ADOPTIVE IMMUNE THERAPY FOR CERVIAL CANCER

Research Project

Project/Area Number 13557160
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section展開研究
Research Field 病態科学系歯学(含放射線系歯学)
Research InstitutionKYOTO UNIVERSITY

Principal Investigator

UMEHARA Hisanori  KYOTO UNIV., ASS.PRO, 医学研究科, 助教授 (70247881)

Co-Investigator(Kenkyū-buntansha) IMAI Toshio  KAN RESEARCH INST., director, カン研究所, 所長
MIMORI Tsuneyo  KYOTO UNIV., PROF., 医学研究科, 教授 (10157589)
堂前 尚親  大阪歯科大学, 歯学部, 教授 (60115889)
Project Period (FY) 2001 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥5,600,000 (Direct Cost: ¥5,600,000)
Fiscal Year 2003: ¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 2002: ¥2,800,000 (Direct Cost: ¥2,800,000)
Keywordsfractalkine / chemokine / NK cells / tumor cytotoxicity / adoptive immune therapy / endothelial cells / 細胞接着 / CD2 / IFN-γ / 細胞傷害 / 頭頸部腫瘍 / fractalkine / 血管傷害
Research Abstract

For the improvement of adoptive immune therapy, we investigated the mechanisms of the major side effects, vascular leak syndrome and functional roles of membrane lipid rafts of NK cells. We found
1) After identification of the receptor for fractalkine, CX3CR1, we reported that CX3CR1 was expressed on CD 14+ monocytes, CD 16+ NK cells and CD8+ T cells.
2) Integrins and fractalkine synergistically enhanced cell adhesion.
3) Fractalkine enhanced cell adhesion and granular exocytosis of NK cells. Fractalkine expressed on activated endothelial cells caused NK cell lysis and vascular injury.
4) Fractalkine activated NK cells and produced IFN-gamma, which may mediate Th1-type immune response.
5) Membrane lipid rafts was involved in cytotoxicity of NK cells.
6) Sphingomyelin of the membrane was important for cellular activation and apoptosis.
These results may provide the new insight for the improvement for adoptive immune therapy by reducing its side effects, vascular leak syndrome, and improved the efficacy of therapy.

Report

(4 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • Research Products

    (54 results)

All Other

All Publications (54 results)

  • [Publications] Yamaoka S, et al.: "Expression cloning of a human cDNA restoring sphingomyelin synthesis and cell growth in sphingomyelin synthase-defective lymphoid cells"J Biol Chem. 印刷中.

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Uchida Y, et al.: "Anthracycline resistance in HL-60/ADR cells via transcriptional up-regulation of glucosylceramide synthase and reversal by Sp1 decoyoligodeoxynucleotides"J.Biol.Chem. 印刷中.

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Umehara H, et al.: "Fractalkine and vascular biology : from basic research to clinical diseases."Arterio.Thromb.Vasc.Biol.(Review).. 24. 34-40 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Watanabe I, et al.: "Increase of the ceramide content in nuclei through caspase-3 dependent inhibition of sphingomyelin synthase in Fas-induced Jurkat T cell apoptosis."Cancer Res.. 60. 1000-1007 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kawabata D, et al.: "Ameliorative effects of follistatin-related protein/TSC-36 on joint inflammation in a mouse model of arthritis."Arthritis Rheum. 50. 660-668 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Iwai K, et al.: "Ceramide increases oxidative damage due to inhibition of catalase by caspase-3-dependent proteolysis in HL-60 cell apoptosis."J.Biol.Chem.. 278. 9813-9822 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Yoneda O, et al.: "Membrane bound form of fractalkine induces IFN-γ production by NK cells : A role for Th1 response."Eur.J.Immunol.. 33. 53-58 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Umehara H, et al.: "Role for adapter proteins in costimulatory signals of CD2 and IL-2 on NK cell activation."Mol.Immunol.. 38. 587-596 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Tanaka Y, et al.: "H-Ras/Mitogen-activated protein kinase pathway inhibits integrin-mediated adhesion and induces apoptosis in osteoblasts."J.Biol.Chem.. 277. 21446-21452 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Nishimura M, et al.: "Dualfunctions of fractalkine/CX3CR1 in trafficking of circulating cytotoxic effector lymphocytes that are defined by CX3CR1 expression."J.Immunol.. 168. 6173-6180 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kondo T, et al.: "Vesnarinone causes oxidative damage by inhibiting catalase function through ceramide action in myeloid cell apoptosis."Mol.Pharm.. 61. 620-627 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kondo T, et al.: "Control of ceramide-induced apoptosis by IGF-1 : involvement of PI-3 kinase, caspase-3 and catalase."Cell Death Differnt. 9. 682-692 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kawase M, et al.: "Increase of ceramide in adriamycin-induced HL-60 cell apoptosis : detection by a novel anti-ceramide antibody."Biochemica et Biophysica Acta. 1584. 104-114 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Inoue H, et al.: "Lipid rafts as the signaling scaffold for NK cell activation : Tyrosine phosphorylation and association of LAT with PI 3-kinase and PLC-γ following CD2 stimulation."Eur.J.Immunol.. 32. 2188-2198 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Yamaoka, S., Miyaji, M., Kitano, T., Umehara, H., Okazaki, T.: "Expression cloning of a human cDNA restoring sphingomyelin synthesis and cell growth in sphingomyelin synthase-defective lymphoid cells."J Biol Chem.. 279. 18688-18693 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Uchida, Y., Itoh, M., Taguchi, Y., Yamaoka, S., Umehara, H., Ichikawa, S., Hirabayashi, Y., Holleran, W., Okazaki, T.: "Anthracycline resistance in HL-60/ADR cells via transcriptional up-regulation of glucosylceramide synthase and reversal by Sp1 decoyoligodeoxynucleotides"J.Biol.Chem.. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Umehara, H., Bloom, E.T., Okazaki, T., Yoshie, O., Imai, T.: "Fractalkine and vascular biology : from basic research to clinical diseases"Arterio.Thromb.Vasc.Biol.. 24. 34-40 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Watanabe, I., Kitano, T., Kondo, T., Yabu, T., Taguchi, Y., Tashima, M., Umehara, H., Domae, N., Uchiyama, T., Okazaki, T.: "Increase of the ceramide content in nuclei through caspase-3 dependent inhibition of sphingomyelin synthase in Fas-induced Jurkat T cell apoptosis."Cancer Res.. 64. 1000-1007 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kawabata, D., Tanaka, M., Fujii, T., Umehara, H., Fuj ita, Y., Yoshifuji, H., Mimori, T., Ozaki, T.: "Ameliorative effects of follistatin-related protein/TSC-36 on joint inflammation in a mouse model of arthritis."Arthritis Rheum.. 50. 660-668 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Iwai, K., Kondo, T., Watanabe, M., Yabu, T., Taguchi, Y., Umehara.H., Takahashi, A., Uchiyama, T., Okazaki, T.: "Ceramide increases oxidative damage due to inhibition of catalase by caspase-3-dependent proteolysis in HL-60 cell apoptosis."J.Biol.Chem.. 278. 9813-9822 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Yoneda, O., Imai, T., Inoue, H., Nishimura, M., Minami, Y., Bloom, E.T., Mimori, T., Domae, N., Umehara, H.: "Membrane bound form of fractalkine induces IFN-γ production by NK cells : A role for Th1 response."Eur.J.Immunol.. 33. 53-58 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Umehara, H., Inoue, H., Huang, J.-Y., Kono, T., Minami, Y., Tanaka, Y., Okazaki, T., Bloom, E.T., Domae, N.: "Role for adapter proteins in costimulatory signals of CD2 and IL-2 on NK cell activation."Mol.Immunol.. 38. 587-596 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Tanaka, Y., Fujimoto, H., Okada, Y., Umehara, H., Katoka, T., Minami, Y.: "H-Ras/Mitogen-activated protein kinase pathway inhibits integrin-mediated adhesion and induces apoptosis in osteoblasts."J.Biol.Chem.. 277. 21446-21452 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Nishirnura, M., Umehara, H., Nakayama, T., Yoneda, O., Hieshima, K., Kakizaki, M., Domae, N., Yoshie, O., Imai, T.: "Dual functions of fractalkine/CX3CR1 in trafficking of circulating cytotoxic effector lymphocytes that are defined by CX3CR1 expression."J.Immunol.. 168. 6173-6180 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kondo, T., Suzuki, Y., Kitano, T., Iwai, K., Watanabe, M., Umehara, H., Daido, N., Domae, N., Tashima, M., Uchiyama, T., Okazaki, T.: "Vesnarinone causes oxidative damage by inhibiting catalase function through ceramide action in myeloid cell apoptosis"Mol.Pharm.. 61. 620-627 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kondo, T., Iwai, K., Kitano, T., Watanabe, M., Taguchi, Y., Yabu, T., Umehara, H., Domae, N., Uchiyama, T., Okazaki, T.: "Control of ceramide-induced apoptosis by IGF-1 : involvement of PI-3 kinase, caspase-3 and catalase."Cell Death Differnt. 9. 682-692 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kawase, M., Watanabe, M., Kondo, T., Yabu, T., Taguchi, Y., Umehara, H., Uchiyama, T., Mizuno, K., Okazaki, T.: "Increase of ceramide in adriamycin-induced HL-60 cell apoptosis : detection by a novel anti-ceramide antibody"BBA. 1584. 104-114 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Inoue, H., Miyaji, M., Kosugi, A., Nagafuku, M., Okazaki, T., Mimori, T., Amakawa, R., Fukuhara, S., Domae, N., Bloom, E., Umehara, H.: "Lipid rafts as the signaling scaffold for NK cell activation : Tyrosine phosphorylation and association of LAT with PI 3-kinase and PLC-γfollowing CD2 stimulation."Eur.J.Immunol.. 32. 2188-2198 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Yamaoka S, et al.: "Expression cloning of a human cDNA restoring sphingomyelin synthesis and cell growth in sphingomyelin synthase-defective lymphoid cells"J Biol Chem. (印刷中).

    • Related Report
      2003 Annual Research Report
  • [Publications] Uchicda Y, et al.: "Anthracycline resistance in HL-60/ADR cells via transcriptional up-regulation of glucosyclceramide synthase and reversal by Sp1 decoyoligodeoxynucleotides"J.Biol.Chem. (印刷中).

    • Related Report
      2003 Annual Research Report
  • [Publications] Umehara H, et al.: "Fractalkine and vascular biology : from basic research to clinical diseases"Arterio.Thromb.Vasc.Biol. (Review). 24. 34-40 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Watanabe I, et al.: "Increase of the ceramide content in nuclei through caspase-3 dependent inhibition of sphingomyelin synthase in Fas-induced Jurkat T cell apoptosis"Cancer Res.. 60. 1000-1007 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kawabata D, et al.: "Ameliorative effects of follistatin-related protein/TSC-36 on joint inflammation in a mouse model of arthritis"Arthritis Rheum. 50. 660-607 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Iwai K, et al.: "Ceramide increases oxidative damage due to inhibition of catalase by caspase-3-dependent proteolysis in HL-60 cell apoptosts"J.Biol.Chem.. 278. 9813-9822 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yoneda O, et al.: "Membrane bound form of fractalkine induces IFN-γ production by NK cells : A role for Th1 response"Eur.J.Immunol.. 33. 53-58 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Umehara H, et al.: "Role for adapter proteins in costimulatory signals of CD2 and IL-2 on NK cells activation"Mol.Tmmunol.. 38. 587-596 (2002)

    • Related Report
      2003 Annual Research Report
  • [Publications] Tanaka Y, et al.: "H-Ras/Mitogen-activated protein kinase pathway inhibits integrin-mediated adhesion and induces apoptosis in osteoblasts"J.Biol.Chem.. 277. 21446-21452 (2002)

    • Related Report
      2003 Annual Research Report
  • [Publications] Nishimura M, et al.: "Dualfunctions of fractalkino/CX3CR1 in trafficking of circulating cytotoxic effector lymphocytes that are defined by CX3CR1 expression"J.Immunol.. 168. 6173-6180 (2002)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kondo T, et al.: "Vesnarinone causes oxidative damage by inhibiting catalase function through ceramide action in myeloid cell apoptosis"Mol.Pharm.. 61. 620-627 (2002)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kondo T, et al.: "Control of ceramide-induced apoptosis by IGF-1 : involvement of PI-3 kinase caspase-3 and catalase"Cell Death Differnt. 9. 682-692 (2002)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kawase M, et al.: "Increase of ceramide in adriamycin-induced HL-60 cell apoptosis detection by a novel anti-ceramido antibody"Biochimica et Biophysica Acta. 1584. 104-114 (2002)

    • Related Report
      2003 Annual Research Report
  • [Publications] Inoue H, et al.: "Lipid rafts as the signaling scaffold for NK cell activation : Tyrosine phosphorylation and association of LAT with PI 3-kinase and PLC-γ following CD2 stimulation"Eur.J.Immunol.. 32. 2188-2198 (2002)

    • Related Report
      2003 Annual Research Report
  • [Publications] Umehara, H: "Role for adapter proteins in costimulatory signals of CD2 and IL-2 on NK cell activation"Mol.Immunol.. 38. 587-596 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Tanaka, Y: "H-Ras/Mitogen-activated protein kinase pathway inhibits integrin-mediated adhesion and induces apoptosis in osteoblasts"J.Biol.Chem.. 277. 21446-21452 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Nishimura, M.: "Dualfunctions of fractalkine/CX3CR1 in trafficking of circulating cytotoxic effector lymphocytes that are defined by CX3CR1"J.Immunol.. 168. 6173-6180 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kondo, T.: "Vesnarinone causes oxidative damage by inhibiting catalase function through ceramide action in myeloid cell"Mol.Pharm.. 61. 620-627 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kondo, T.: "Control of ceramide-induced apoptosis by IGF-1 : involvement of PI-3 kinase, caspase-3 and catalase"Cell Death Differnt. 9. 682-692 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kawase, M.: "Increase of ceramide in adriamycin-induced HL-60 cell apoptosis : detection by a novel anti-ceramide antibody"BBA. 1584. 104-114 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Umehara, H.: "Fractalkine and vascular injury"Trends Immunol.. 22. 602-607 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Umehara, H.: "Fractalkine, a CX3C-chemokine, functions predominantly as an adhesion molecule in monocytic cell line THP-1"Immunol.Cell Biol.. 79. 298-302 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Umehara, H.: "The role of fractalkine in leukocyte adhesion and migration, and vascular injury"Drug News & Perspectives. 14. 460-464 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Umehara, H.: "Role for adapter proteins in costimulatory signals of CD2 and IL-2 on NK cell activation"Mol.Immunol.. 38. 587-596 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 梅原久範: "フラクタルカインの基礎と臨床"臨床免疫. 35. 353-359 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 梅原久範: "フラクタルカイン"臨床検査. 45. 73-76 (2001)

    • Related Report
      2001 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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