1997 年度実績報告書

がん免疫寛容のメカニズムとその制御

研究課題

研究課題/領域番号	06282103
研究機関	千葉大学
研究代表者	谷口克千葉大学, 医学部, 教授 (80110310)
研究分担者	石川哮熊本大学, 医学部, 教授 (00009143) 西村孝司東海大学, 医学部, 助教授 (30143001) 藤原大美大阪大学, 医学部, 助教授 (70116094) 奥村康順天堂大学, 医学部, 教授 (50009700) 西村泰治熊本大学, 医学部, 教授 (10156119)
キーワード	がん免疫 / トレランス / サイトカイン / NKT細胞 / IL-12 / 養子免疫療法
研究概要	がんに対する末梢性免疫寛容成立の機序とその制御メカニズムを検討した。そのために、(1)抗原認識分子を介する末梢性免疫寛容成立機序をその人為的阻害の基礎研究、(2)免疫制御細胞による末梢性免疫寛容性の機序とその制御に関する研究、(3)特異的CTLを用いた養子免疫による末梢性免疫寛容からの回復を目指したがん治療法の開発を行った。その結果、 1.がん化に関与するがん遺伝子産物、がん抑制遺伝子産物のMHC結合ペプチドおよびそのアナログペプチドを同定した。 2.CD40L遺伝子導入によるがん拒絶の促進IL-12サイトカインによる腫瘍内血管接着分子の発現増強など、補助受容体サイトカイン受容体を介する腫瘍退宿経路が明らかとなった。 3.T細胞による腫瘍拒絶においてTh1は細胞免疫型Th2は炎症性壊死反応によることを明らかにした。 4.NKT細胞は腫瘍拒絶の強力な細胞であり、IL-12の直接の標的細胞はNKT細胞であった。 5.上顎癌に対する養子免疫療法によって約60%(14/24例)が完全消失し、全例(24例)で効果を認め、極めて効果的であることを実証。一方マウスモデルではCD8,CD4T細胞がともに必要であることを見いだした。

研究成果
(28件)

すべてその他

すべて文献書誌 (28件)

[文献書誌] Kawano,T: "CD1d-restricted and TCR-mediated activation of Vα14 NKT cells by glycosylceramides." Science. 278. 1626-1629 (1997)
[文献書誌] Cui,J.: "Requirement for Vα14 NKT cells in IL-12-mediated rejection of tumors." Science. 278. 1623-1626 (1997)
[文献書誌] Fujita,H.: "Evidence that HLA class ll-restricted human CD^+ T-cells specific to p53 self peptides respond to p53 proteins of both wild and mutant forms." Eur. J. Immunol.(in press).
[文献書誌] Yokomizo,H.: "Augmentation of immune response by an analog of the antigenic peptide in a human T-cell clone recognizing mutated Ras-derived peptides." Human Immunol.52. 22-32 (1997)
[文献書誌] Fujisao,S.: "Evaluation of peptide-HLA bindingby an enzyme-linked assay and its application to the detailed peptide motifs for HLA-DR9(DRB1^★0901)." Immunol. Meth.201. 157-163 (1997)
[文献書誌] Fujisao,S.: "Identification of HLA-DR9(DRB1^★0901)-binding peptide motifs using a phage fUSE5 random peptide library." Human Immunol.45. 131-136 (1996)
[文献書誌] Seino,K.: "Antitumor effect of locally produced CD95 ligand." Nature Med.3. 165-170 (1997)
[文献書誌] Enomoto,A.: "Adoptive transfer of cytotoxic T lymphocytes induced by CD86-transfected tumor cells suppresses multi-organ metastases of C1300neuroblastoma in mice" Cancer Immunol. Immunother.44. 204-210 (1997)
[文献書誌] Maruo,S.: "B cells regulate CD40 ligand-induced IL-12 production in antigen-presenting cells (APC) during T cell-APC interactions." J. Immunol.158. 120-126 (1997)
[文献書誌] Takenaka,H.: "Regulation of T cell-dependent and -independent IL-12 production by three Th2-type cytokinesIL-10, IL-6 and IL-4." J. Leukocyte Biol.61. 80-87 (1997)
[文献書誌] Maruo,S.: "Establishment of an IL-12-dependent T cell clone : Its characterization and utilization to quantitation of IL-12 activity." J. Leukocyte Biol.61. 346-352 (1997)
[文献書誌] Ogawa,M.: "Enhanced induction of VLA-4/LFA-1-dependent T cell migration to tumor sites following administration of IL-12." Cancer Res.57. 2216-2222 (1997)
[文献書誌] Fujiwara,H.: "The anti-tumor effects of IL-12 involve enhanced IFN-γ production by anti-tumor T cells, their accumulation to tumor sites and in situ IFN-γ production." Leukemia 11. Suppl. 3. 570-571 (1997)
[文献書誌] Ahn,H-J.: "A mechanism underlying synergy between IL-12, and IFN-γ-inducing factor in enhanced production of IFN-γ." J. Immunol.159. 2125-2131 (1997)
[文献書誌] Tsutsui,T.: "Administration of IL-12 induces a CD3^+CD4CD8B220^+ lymphoid population capable of eliciting cytolysis against Fas-positive tumor cells." J. Immunol.159. 2599-2605 (1997)
[文献書誌] Yu,W-G.: "IL-12-induced tumor regression corretates with in situ activity of IFN-γ produced by tumor-infiltrating cells and its. secondary induction of anti-tumor pathways." J. Leukoc. Biol.62. 450-457 (1997)
[文献書誌] Yahata,T.: "Accumulation of IL-12-activated antitumor effector cells into lymph nodes of tumor-bearing mice." Immunol. Letters. (in press).
[文献書誌] Ohta,A.: "Maniputation of Th1/Th2 balance in vivo by adoptive transfer of antigen-specific Th1 or Th2 cells." J. Immunol. Meth.(in press).
[文献書誌] Ohmi,Y.: "The role of phorbol ester-sensitive protein kinase C isoforms in lymphokine-activated killer cell-mediated cytotoxicity : Dissociation between perforin-dependent and Fas-dependent cytotoxicity." Biochem. Biophys. Res. Commun.235. 461-464 (1997)
[文献書誌] Nishimura,T.: "Involvement of IL-4 producing Vβ8.2^+CD4^+ CD62L^<-->CD45RB^- T cells in non-MHC gene controlled predisposition toward skewing into T helper type-2 immunity in BALB/c mice." J. Immunol.158. 5698-5706 (1997)
[文献書誌] Tanaka,Y.: "Productive and lytic infection of human CD4^+ type 1 helper T cells with macrophage-tropic human immuno-deficiency virus type1." J. Virol.71. 465-470 (1997)
[文献書誌] Sato,N.: "Functional character-ization of Ly-6C^+NK1.1^+ cells." Immunol. Letters. 54. 5-9 (1996)
[文献書誌] Nishimura,T.: "The application of IL-12 to antitumor cytokine and gene therapy." Cancer Chemother. Pharmacol.38. S27-S34 (1996)
[文献書誌] Lee,U.: "Munne asialo GM1^+CD8^+T cells as novel interleukin-12-responding killer T cell precursors." Jpn. J. Cancer Res.87. 429-432 (1996)
[文献書誌] Lee,K.D.: "Expression of the MAGE-1, -2, -3, -4, and -6, genes in non-squamous cell carcinoma lesions of the head and neck." Acta Otolaryngol(Stockh). 116. 633-639 (1996)
[文献書誌] Ishikawa,T.: "Induction of cytotoxic T lympho-cytes(CTL)specific to autologous squamous cell carcinoma from head and neck cancer patients." XVI World Congress of Otorhinolaryngology Head and Neck Surgery. 1231-1235 (1997)
[文献書誌] Shen,Y.: "A tumor-specific Th2 clone initiating tumor rejection via primed CD8^+ cytotoxic T-lymphocyte activation in the mouse." Cancer Res.56. 5005-5011 (1996)
[文献書誌] Saito,S.: "Induction of specific cytotoxic T lymphocyte against autologous brain tumor by crossreactive allo-tumor cell stimulation." JPN. J. Cancer Res.88. 289-295 (1997)

1997 年度 実績報告書

がん免疫寛容のメカニズムとその制御

研究代表者

谷口 克 千葉大学, 医学部, 教授 (80110310)

研究成果

[文献書誌] Kawano,T: "CD1d-restricted and TCR-mediated activation of Vα14 NKT cells by glycosylceramides." Science. 278. 1626-1629 (1997)

[文献書誌] Cui,J.: "Requirement for Vα14 NKT cells in IL-12-mediated rejection of tumors." Science. 278. 1623-1626 (1997)

[文献書誌] Fujita,H.: "Evidence that HLA class ll-restricted human CD^+ T-cells specific to p53 self peptides respond to p53 proteins of both wild and mutant forms." Eur. J. Immunol.(in press).

[文献書誌] Yokomizo,H.: "Augmentation of immune response by an analog of the antigenic peptide in a human T-cell clone recognizing mutated Ras-derived peptides." Human Immunol.52. 22-32 (1997)

[文献書誌] Fujisao,S.: "Evaluation of peptide-HLA bindingby an enzyme-linked assay and its application to the detailed peptide motifs for HLA-DR9(DRB1^★0901)." Immunol. Meth.201. 157-163 (1997)

[文献書誌] Fujisao,S.: "Identification of HLA-DR9(DRB1^★0901)-binding peptide motifs using a phage fUSE5 random peptide library." Human Immunol.45. 131-136 (1996)

[文献書誌] Seino,K.: "Antitumor effect of locally produced CD95 ligand." Nature Med.3. 165-170 (1997)

[文献書誌] Enomoto,A.: "Adoptive transfer of cytotoxic T lymphocytes induced by CD86-transfected tumor cells suppresses multi-organ metastases of C1300neuroblastoma in mice" Cancer Immunol. Immunother.44. 204-210 (1997)

[文献書誌] Maruo,S.: "B cells regulate CD40 ligand-induced IL-12 production in antigen-presenting cells (APC) during T cell-APC interactions." J. Immunol.158. 120-126 (1997)

[文献書誌] Takenaka,H.: "Regulation of T cell-dependent and -independent IL-12 production by three Th2-type cytokinesIL-10, IL-6 and IL-4." J. Leukocyte Biol.61. 80-87 (1997)

[文献書誌] Maruo,S.: "Establishment of an IL-12-dependent T cell clone : Its characterization and utilization to quantitation of IL-12 activity." J. Leukocyte Biol.61. 346-352 (1997)

[文献書誌] Ogawa,M.: "Enhanced induction of VLA-4/LFA-1-dependent T cell migration to tumor sites following administration of IL-12." Cancer Res.57. 2216-2222 (1997)

[文献書誌] Fujiwara,H.: "The anti-tumor effects of IL-12 involve enhanced IFN-γ production by anti-tumor T cells, their accumulation to tumor sites and in situ IFN-γ production." Leukemia 11. Suppl. 3. 570-571 (1997)

[文献書誌] Ahn,H-J.: "A mechanism underlying synergy between IL-12, and IFN-γ-inducing factor in enhanced production of IFN-γ." J. Immunol.159. 2125-2131 (1997)

[文献書誌] Tsutsui,T.: "Administration of IL-12 induces a CD3^+CD4CD8B220^+ lymphoid population capable of eliciting cytolysis against Fas-positive tumor cells." J. Immunol.159. 2599-2605 (1997)

[文献書誌] Yu,W-G.: "IL-12-induced tumor regression corretates with in situ activity of IFN-γ produced by tumor-infiltrating cells and its. secondary induction of anti-tumor pathways." J. Leukoc. Biol.62. 450-457 (1997)

[文献書誌] Yahata,T.: "Accumulation of IL-12-activated antitumor effector cells into lymph nodes of tumor-bearing mice." Immunol. Letters. (in press).

[文献書誌] Ohta,A.: "Maniputation of Th1/Th2 balance in vivo by adoptive transfer of antigen-specific Th1 or Th2 cells." J. Immunol. Meth.(in press).

[文献書誌] Ohmi,Y.: "The role of phorbol ester-sensitive protein kinase C isoforms in lymphokine-activated killer cell-mediated cytotoxicity : Dissociation between perforin-dependent and Fas-dependent cytotoxicity." Biochem. Biophys. Res. Commun.235. 461-464 (1997)

[文献書誌] Nishimura,T.: "Involvement of IL-4 producing Vβ8.2^+CD4^+ CD62L^<-->CD45RB^- T cells in non-MHC gene controlled predisposition toward skewing into T helper type-2 immunity in BALB/c mice." J. Immunol.158. 5698-5706 (1997)

[文献書誌] Tanaka,Y.: "Productive and lytic infection of human CD4^+ type 1 helper T cells with macrophage-tropic human immuno-deficiency virus type1." J. Virol.71. 465-470 (1997)

[文献書誌] Sato,N.: "Functional character-ization of Ly-6C^+NK1.1^+ cells." Immunol. Letters. 54. 5-9 (1996)

[文献書誌] Nishimura,T.: "The application of IL-12 to antitumor cytokine and gene therapy." Cancer Chemother. Pharmacol.38. S27-S34 (1996)

[文献書誌] Lee,U.: "Munne asialo GM1^+CD8^+T cells as novel interleukin-12-responding killer T cell precursors." Jpn. J. Cancer Res.87. 429-432 (1996)

[文献書誌] Lee,K.D.: "Expression of the MAGE-1, -2, -3, -4, and -6, genes in non-squamous cell carcinoma lesions of the head and neck." Acta Otolaryngol(Stockh). 116. 633-639 (1996)

[文献書誌] Ishikawa,T.: "Induction of cytotoxic T lympho-cytes(CTL)specific to autologous squamous cell carcinoma from head and neck cancer patients." XVI World Congress of Otorhinolaryngology Head and Neck Surgery. 1231-1235 (1997)

[文献書誌] Shen,Y.: "A tumor-specific Th2 clone initiating tumor rejection via primed CD8^+ cytotoxic T-lymphocyte activation in the mouse." Cancer Res.56. 5005-5011 (1996)

[文献書誌] Saito,S.: "Induction of specific cytotoxic T lymphocyte against autologous brain tumor by crossreactive allo-tumor cell stimulation." JPN. J. Cancer Res.88. 289-295 (1997)

1997 年度実績報告書

谷口克千葉大学, 医学部, 教授 (80110310)