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導入遺伝子の長期発現増強法を用いた転移性癌の遺伝子治療法の開発

Research Project

Project/Area Number 13218069
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionOsaka University

Principal Investigator

金田 安史  大阪大学, 医学系研究科, 教授 (10177537)

Project Period (FY) 2001 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥40,400,000 (Direct Cost: ¥40,400,000)
Fiscal Year 2004: ¥10,100,000 (Direct Cost: ¥10,100,000)
Fiscal Year 2003: ¥10,100,000 (Direct Cost: ¥10,100,000)
Fiscal Year 2002: ¥10,000,000 (Direct Cost: ¥10,000,000)
Fiscal Year 2001: ¥10,200,000 (Direct Cost: ¥10,200,000)
KeywordsHVJ / 樹状細胞 / 融合細胞 / CGオリゴヌクレオチド / 癌ワクチン / 細胞傷害性T細胞 / HVJ-E / 遺伝子導入 / CTL / トランスポゾン / トランスポゼース / ヒストン脱アセチル化酵素阻害剤 / HVJ-liposome / HVJ envelope vector / 悪性黒色腫 / 癌関連抗原 / ヒストン脱アセチル化酵素 / 抗癌剤 / 自殺遺伝子治療 / Epstein-Barr virus / 長期遺伝子発現
Research Abstract

癌抗原関連遺伝子が同定されていない癌に対し、PEGや電気穿孔法を用いた癌細胞と樹状細胞の融合法が抗腫瘍免疫誘導に有効であること報告されている。しかし、不活性化HVJはそれよりも再現性高くまた高効率に(PEGの数十倍)融合させることが可能であった。融合細胞をマウス皮下に1週間隔で2度免疫し10日後に脾細胞を取り出し、癌細胞で刺激したときに分泌されるIL-12を測定した。樹状細胞と癌細胞の混合したもので免疫したものよりも高いサイトカイン分泌を得た。融合細胞だけをソーティングしてもしなくてもサイトカイン分泌は変わらなかった。この融合細胞により癌の抗原の多くが提示されると考えられるが、その後でNaive T細胞を成熟させて細胞傷害性T細胞として機能させるため、アジュバンド作用のある物質が必要である。そこでCpGオリゴヌクレオチドを用いることにした。CpGオリゴヌクレオチドを融合細胞と混合したところ、CD80,CD86,MHC-class IIの発現でみられる樹状細胞の成熟がさらに増強され、IL-12,TNF-alphaの分泌もCpGオリゴヌクレオチドを用いない場合の2倍以上であった。そこでX線照射したマウスメラノーマとマウス樹状細胞の融合細胞をCpGオリゴヌクレオチドと混合してマウスに2度投与し、10日後に脾細胞を取り出してメラノーマに対する細胞傷害性T細胞の活性を測定したところ、CpGオリゴヌクレオチドの併用により著しい活性の増強をみた。しかしこの細胞傷害性T細胞は同じ系統のマウス異なる腫瘍であるリンフォーマ細胞EL4には反応しなかった。免疫後に腫瘍を移植したところこの方法により癌生着の完全抑制、高いマウス生存率(80%)が得られた。マウス腎癌細胞RENCAを用いた場合も同様のワクチン効果が得られた。腫瘍ができなかったマウスに再度同じ腫瘍を移植しても完全に拒絶がおこった。

Report

(4 results)
  • 2004 Annual Research Report
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • Research Products

    (29 results)

All 2004 2001 Other

All Journal Article (6 results) Book (1 results) Patent(Industrial Property Rights) (1 results) Publications (21 results)

  • [Journal Article] Enhanced tumor-specific long-term immunity of HVJ-mediated DC-tumor fused cell vaccination by coadministration with CpG oligodeoxynucleotides.2004

    • Author(s)
      Hiraoka, K.
    • Journal Title

      J.Immunology 173

      Pages: 4297-4307

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Transposon-independent enhancement of transcription by Sleeping Beauty transposase.2004

    • Author(s)
      Masuda, K.
    • Journal Title

      Biochem.Biophys.Res.Comm. 317

      Pages: 796-800

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Hemagglutinating virus of Japan protein is efficient for induction of CD4+ T-cell response by a hepatitis B core particle-based HIV vaccine.2004

    • Author(s)
      Takeda, S.
    • Journal Title

      Clinical Immunology 112

      Pages: 92-105

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Essential role of HGF (hepatocyte growth factor) in blood formation in Xenopus.2004

    • Author(s)
      Koibuchi, N.
    • Journal Title

      Blood 103

      Pages: 3320-3325

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Intrathecal injection of HVJ-E containing HGF gene to cerebrospinal fluid can prevent and ameliorate hearing impairment in rats.2004

    • Author(s)
      Oshima, K.
    • Journal Title

      The FASEB J. 18

      Pages: 212-214

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Biocompatible polymer enhances the in vitro and in vivo transfection efficiency of HVJ envelone vector

    • Author(s)
      Mima, H.
    • Journal Title

      J.Gene Medicine (in press)

    • Related Report
      2004 Annual Research Report
  • [Book] Polymeric Gene Delivery2004

    • Author(s)
      Yasufumi Kaneda
    • Total Pages
      685
    • Publisher
      CRC PRESS
    • Related Report
      2004 Annual Research Report
  • [Patent(Industrial Property Rights)] 遺伝子導入のためのウイルスエンベロープベクター2001

    • Inventor(s)
      金田 安史
    • Industrial Property Rights Holder
      金田 安史, ジェノミディア
    • Filing Date
      2001-02-02
    • Acquisition Date
      2004-05-06
    • Related Report
      2004 Annual Research Report
  • [Publications] Ishida, C.: "Genomic organization and promoter analysis of the Dnmt3b gene."Gene. 310. 151-159 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Nakabayashi, M.: "HGF/NK4 inhibited VEGF-induced angiogenesis in in vitro cultured endothelial cells and in vivo rabbit model."Diabetologia. 46. 115-123 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Shimamura, M: "HVJ-envelope vector for gene transfer into central nervous system."Biochem.Biophys.Res.Comm.. 300. 464-471 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Koike, H.: "Enhanced angiogenesis and improvement of neuropathy by cotransfection of human hepatocyte growth factor and prostacyclin synthase gene."The FASEB J.. 17. 779-781 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yamamoto, S.: "A novel combination of suicide gene therapy and histone deacetylase inhibitor for treatment of malignant melanoma."Cancer Gene Therapy. 10. 179-186 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Oshima, K.: "Intrathecal injection of HVJ-E containing HGF gene to cerebrospinal fluid can prevent and ameliorate hearing impairment in rats."The FASEB J.. (in press).

    • Related Report
      2003 Annual Research Report
  • [Publications] Kaneda, Y.: "Methods in ENZYMOLOGY"ELSEVIER. 596 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yamamoto, S.: "A novel combination of suicide gene therapy and histone deacetylase inhibitor for treatment of malignant melanoma"Cancer Gene Therapy. (in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Tomita, N.: "Targeted Gene Therapy for Rat Glomerulonephritis using HVJ-immunoliposomes"J. Gene Medicine. 4. 527-535 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kaneda, Y.: "HVJ (hemagglutinating virus of Japan) envelope vector as a versatile gene delivery system"Molecular Therapy. 6. 219-226 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Tanaka, M.: "Induction of a systemic Immune response by a polyvalent melanoma-associated antigen DNA vaccine for prevention and treatment of malignant melanoma"Molecular Therapy. 5. 291-299 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Endoh, M.: "Fetal gene transfer by intra-uterine injection with microbubble-enhanced ultrasound"Molecular Therapy. 5. 501-505 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Taniyama Y.: "Local delivery of plasmid DNA into rat carotid artery using ultrasound"Circulation. 105. 1233-1239 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kaneda, Y.: "Pharmaceutical Gene Delivery Systems"Alain Rolland and Sean Sullivan(in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Hirano, T., Kaneko, S., Kaneda, Y., et al.: "HVJ-liposome mediated transfection of HSVtk gene driven by AFP promoter Inhibits hepatic tumor growth of hepatocellular carcinoma in SCID mice"Gene Therapy. 8. 80-83 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Otomo, T., Yamamoto, S., Morishita, R., Kaneda, Y.: "EBV replicon vector system enhances transgene expression in vivo : applications to gene therapy for cancer"J. Gene Med.. 3. 345-352 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kawamura, I., Kaneda, Y., et al.: "Intravenous injection of oligodeoxynucleotides to the NF-kappaB binding site inhibits hepatic metastasis of M5076 reticulosarcoma in mice"Gene therapy. 8. 905-912 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kaneko, K., Kaneda, Y., Monden, M., et al.: "Detection of peritoneal micrometastases of gastric carcinoma with green fluorescent protein and carcinoembryonic antigen promoter"Cancer Res.. 61. 5570-5574 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Hasegawa, H., Kaneda, Y., Sugimachi, K., et al.: "Preclinical and therapeutic utility of HVJ liposomes as a gene transfer vector for hepatocellular carcinoma using herpes simplex virus thymidine kinase"Cancer Gene Therapy. 8. 252-258 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Miyata.T, Kaneda, Y., et al.: "Novel immunotherapy for peritoneal dissemination of murine colon cancer with macrophage inflammatory protein-1§mediated by a tumor-specific vector, HVJ-cationic liposomes"Cancer Gene Therapy. 8. 852-860 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kaneda, Y.: "Frontiers in Human Genetics"World Scientific. 396 (2001)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2018-03-28  

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