1997 Fiscal Year Annual Research Report

がん免疫寛容のメカニズムとその制御

Research Project

Project/Area Number	06282103
Research Institution	Chiba University
Principal Investigator	谷口克千葉大学, 医学部, 教授 (80110310)
Co-Investigator(Kenkyū-buntansha)	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)
Keywords	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
Research Abstract	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。

Research Products

(28 results)

All Other

All Publications (28 results)

[Publications] Kawano,T: "CD1d-restricted and TCR-mediated activation of Vα14 NKT cells by glycosylceramides." Science. 278. 1626-1629 (1997)
[Publications] Cui,J.: "Requirement for Vα14 NKT cells in IL-12-mediated rejection of tumors." Science. 278. 1623-1626 (1997)
[Publications] 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).
[Publications] 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)
[Publications] 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)
[Publications] Fujisao,S.: "Identification of HLA-DR9(DRB1^★0901)-binding peptide motifs using a phage fUSE5 random peptide library." Human Immunol.45. 131-136 (1996)
[Publications] Seino,K.: "Antitumor effect of locally produced CD95 ligand." Nature Med.3. 165-170 (1997)
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] Yahata,T.: "Accumulation of IL-12-activated antitumor effector cells into lymph nodes of tumor-bearing mice." Immunol. Letters. (in press).
[Publications] Ohta,A.: "Maniputation of Th1/Th2 balance in vivo by adoptive transfer of antigen-specific Th1 or Th2 cells." J. Immunol. Meth.(in press).
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] Sato,N.: "Functional character-ization of Ly-6C^+NK1.1^+ cells." Immunol. Letters. 54. 5-9 (1996)
[Publications] Nishimura,T.: "The application of IL-12 to antitumor cytokine and gene therapy." Cancer Chemother. Pharmacol.38. S27-S34 (1996)
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] 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 Fiscal Year Annual Research Report

がん免疫寛容のメカニズムとその制御

Principal Investigator

谷口 克 千葉大学, 医学部, 教授 (80110310)

Research Products

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

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

[Publications] 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).

[Publications] 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)

[Publications] 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)

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

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

[Publications] 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)

[Publications] 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)

[Publications] 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)

[Publications] 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)

[Publications] 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)

[Publications] 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)

[Publications] 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)

[Publications] 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)

[Publications] 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)

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

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

[Publications] 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)

[Publications] 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)

[Publications] 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)

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

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

[Publications] 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)

[Publications] 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)

[Publications] 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)

[Publications] 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)

[Publications] 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)

谷口克千葉大学, 医学部, 教授 (80110310)