1998 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, 大学院・医学研究所, 教授 (80110310)
研究分担者	江浦正郎熊本大学, 医学部附属病院, 講師 (60193984) 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 / ドレランス / 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と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研究、の3つの観点から研究を行い、下記の諸点を明らかにした。 1) TEL/AMLl融合ペプチドの1アミノ酸置換アナログペプチドは、CD4T細胞の活性化/IFNγ産生を約10倍に増強した。 2) CD40L遺伝子導入により、IL-12によるNK/NKT細胞の活性化、B7発現誘導による特異的T細胞活性化を起こし、特異的抗腫瘍免疫を効果的に誘導できた。 3) IL-12治療による腫瘍退縮には、peritumoralストローマ血管の接着分子発現増強とそれによるT細胞が腫瘍塊に浸潤が必要であった。 4) NKTリガンドα-GalCerは、CD40/CD40L依存的にDCのIL-12産生とNKTのIL-12受容体を発現増強させ免疫増強効果を出す。さらに、IL-12とα-GalCerとの併用は相乗的に働き、IFNγ産生/NK活性化が著しく増強され、癌治療への有用性が示された。 5) ヒトNKT細胞のリガンドもα-GalCerである事を証明し、活性化ヒトNKT細胞は広範にヒト腫瘍を障害し臨床応用に道を開いた。 6) MAGE-3抗原由来のHLA-A24分子結合性癌拒絶抗原を新しく同定した。しかしながら、頭頸部扁平上皮癌患者においてペプチド特異的CTLの誘導は困難であった。 7) 特異的CD4T細胞とCD8CTLの協同作用で最も強い腫瘍の拒絶がみられた。それは担癌末期状態で低下するCD8T細胞のCD3zeta分子の表現をCD4T細胞が回復し、CTLを活性化する事を見い出した。

研究成果
(30件)

すべてその他

すべて文献書誌 (30件)

[文献書誌] Kawano,T.: "A novel recognition motif of human NKT cell receptors for a qlvcolipid ligand." Int.Immunol.(In press).
[文献書誌] Burdin,N.: "Selective ability of mouse CD1 to present glycolipids: α-galactosylceramide specifically stimulates Vα14 NKT lymphocye" J.Immunol.161. 3271-3281 (1998)
[文献書誌] Kawano,T.: "NK-like nonspecific tumor cell lysis mediated by specific ligand-activated Vα14 NKT cells" Proc.Natl.Acad.Sci.USA. 95. 5690-5693 (1998)
[文献書誌] Fujita,H.: "Evidence that HLA class II-restricted humanCD4+ T-cells specific to p53 self peptides respond to p53 proteins of both wild and mutant froms." Eur.J.Immunol.28. 305-316 (1998)
[文献書誌] Yasukawa,M.: "CD4+ cytotoxic T-cell clones specific for bcr-abl b3a2 fusion peptide augment eolony formation by chronic myelogenous leukemia cells in a b3a2-specific and HEA DR-restricted manne" Blood. 92. 3355-3361 (1998)
[文献書誌] Zeki,K.: "Induction of expression of MHC-class-II antigen on human thyroid carcinoma by wild-type.p53" Int.J.Cancer. 75. 391-395 (1998)
[文献書誌] Tanaka,Y.: "Effecient induction of human CD4+ T cell lines reactive with a self-K-ras-derived peptide in vitro,using a mAb to CD29" Human Immunol.52. 179-182 (1998)
[文献書誌] Ono,T.: "Molecular analysis of HLA class I (HLA-A and -B) and HLA class II (HLA-A-DRB1) genes in Japanese patients with multipees sclerosis" Tissue Antigens. 52. 539-542 (1998)
[文献書誌] Fujii,S.: "The CLIP-substituted invariant chain efficiently targets an antigenic peptide to HLA class II pathway in L cell" Human Immunol.59. 607-614 (1998)
[文献書誌] Tabata,H.: "Characterization of self-glutamic acid decarboxylese 65-reactive CD4+ T cell clones established from Japanese patients with insulin dependent diabetes mellitus" Human Immunol.59. 549-560 (1998)
[文献書誌] Nishimura,Y.: "Modification of human T cell responses by altered peptide ligands a new approach to antigen-specific modification" Internal Medicine. 37. 804-817 (1998)
[文献書誌] Kawamura,T.: "Critical role of NK1+ T cells in IL-I2-induced immune response in vivo" J.Immunol.160. 16-19 (1998)
[文献書誌] Mogi,S.: "Efficient generation of autologous peripheral blood-derived cytotoxic T lymphocytes against poorlyimmunogenic human tumors using recombinant CD80-adenovirous together with interleukin 12 and interleukin 2." Cli.Cancer Res.4. 713-720 (1998)
[文献書誌] Nakajima,A.: "Antitumor effect of CD40 ligand: elicitaton of local and sytemic antitumor responses by IL-I2 and B7" J.Immunol.161. 1901-1907 (1998)
[文献書誌] Judo,S.: "Elevated serum levels of soluble of Fas/APO-1 (CD95) in patients with hepatocellular cartinoma" Clin.Exp.Immunol.112. 166-171 (1998)
[文献書誌] Ogawa,M.: "Multiple roles of IFN-γ in the mediation of IL-I2-induced tumor regression" Cancer Res.58. 2426-2432 (1998)
[文献書誌] Wijesuriya,R.: "B cell-mediated down-reglulation of IFN-γ and IL-I2 production induced during anti-tumor immune responses in the tumor-bearing" Int.Immunol.10. 1057-1065 (1998)
[文献書誌] Ahn,H-J.: "Reguirement for distinct Janus kinases and STAT proteins in T cell proliferation vs IFN-γ production following IL-I2 stimulation" J.Immunol.161. 5893-5900 (1998)
[文献書誌] Ogawa,M.: "A critical role for a peritrumoral stomal reaction in the induction of T cell migration responsible for IL-I2-induced tumor regression" Cancer Res.(In press).
[文献書誌] Fujiwara,H.: "Molecular mechanisms underlying T cell migration responsible for IL-I2-induced tumor regression" Gann Monogr.Cancer Res.(In press).
[文献書誌] Kitamura,H.: "The natural Killer T (NKT) cell ligand α-galactosylceramide demonstrates its immunopotentiating effect by inducing IL-I2..." J.Exp.Med.(In press).
[文献書誌] Yahata,T.: "The essential role of phorbol ester-sensitive protein kinase C isoforms in activation-induced cell death of Th1 cells" Eur.J.Immunol.(In press).
[文献書誌] Sato,M.: "Functional skewing of bone marrow-derived dendritic cells by Th1- or Th2-inducing cytokines" Immunol.Lett.(In press).
[文献書誌] Yahata,T.: "Reconsititution of immune systems in RAG2 -/- mice by transfer with interleukin-l2-induced splenic hematopoietic progenitor cell" Immunol.Lett.62. 165-170 (1998)
[文献書誌] Iwakabe,K.: "The restrain stress derives a shift in Th1/Th2 balance toward Th2-dominant immunity in mice" Immunol.Lett.62. 39-43 (1998)
[文献書誌] Yahata,T.: "Accumulation of IL-I2-activated antitumor effector cells into lymph nodes of tumor-bearing mice" Immunol.Lett.61. 127-133 (1998)
[文献書誌] Oiso,M.: "A newly identified MAGE-3-derived epitope recognized by HLA-A24 restricted cytotoxic T lymphocytes" Int.J.Cancer. (In press).
[文献書誌] Shen,Y.: "A tumor-specific Th2 clone intiating tumor rejection via primed CD8+ cytotoxic T-lymphocyte activation in the mouse" Cancer Res.56. 5005-5011 (1996)
[文献書誌] Satio,S.: "Induction of specific tytotoxic T lymphocyte against autologous brain tumor by crossreactive allo-tumor cell stimulation" Jpn.J.Cancer Res.88. 289-295 (1997)
[文献書誌] Jiao,Y.: "Sequential T cell response involved in tumor rejection of sarcoma meth A in syngeneic mice" Jpn.J.Cancer Res.89. 657-665 (1998)

1998 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, 大学院・医学研究所, 教授 (80110310)

研究成果

[文献書誌] Kawano,T.: "A novel recognition motif of human NKT cell receptors for a qlvcolipid ligand." Int.Immunol.(In press).

[文献書誌] Burdin,N.: "Selective ability of mouse CD1 to present glycolipids: α-galactosylceramide specifically stimulates Vα14 NKT lymphocye" J.Immunol.161. 3271-3281 (1998)

[文献書誌] Kawano,T.: "NK-like nonspecific tumor cell lysis mediated by specific ligand-activated Vα14 NKT cells" Proc.Natl.Acad.Sci.USA. 95. 5690-5693 (1998)

[文献書誌] Fujita,H.: "Evidence that HLA class II-restricted humanCD4+ T-cells specific to p53 self peptides respond to p53 proteins of both wild and mutant froms." Eur.J.Immunol.28. 305-316 (1998)

[文献書誌] Yasukawa,M.: "CD4+ cytotoxic T-cell clones specific for bcr-abl b3a2 fusion peptide augment eolony formation by chronic myelogenous leukemia cells in a b3a2-specific and HEA DR-restricted manne" Blood. 92. 3355-3361 (1998)

[文献書誌] Zeki,K.: "Induction of expression of MHC-class-II antigen on human thyroid carcinoma by wild-type.p53" Int.J.Cancer. 75. 391-395 (1998)

[文献書誌] Tanaka,Y.: "Effecient induction of human CD4+ T cell lines reactive with a self-K-ras-derived peptide in vitro,using a mAb to CD29" Human Immunol.52. 179-182 (1998)

[文献書誌] Ono,T.: "Molecular analysis of HLA class I (HLA-A and -B) and HLA class II (HLA-A-DRB1) genes in Japanese patients with multipees sclerosis" Tissue Antigens. 52. 539-542 (1998)

[文献書誌] Fujii,S.: "The CLIP-substituted invariant chain efficiently targets an antigenic peptide to HLA class II pathway in L cell" Human Immunol.59. 607-614 (1998)

[文献書誌] Tabata,H.: "Characterization of self-glutamic acid decarboxylese 65-reactive CD4+ T cell clones established from Japanese patients with insulin dependent diabetes mellitus" Human Immunol.59. 549-560 (1998)

[文献書誌] Nishimura,Y.: "Modification of human T cell responses by altered peptide ligands a new approach to antigen-specific modification" Internal Medicine. 37. 804-817 (1998)

[文献書誌] Kawamura,T.: "Critical role of NK1+ T cells in IL-I2-induced immune response in vivo" J.Immunol.160. 16-19 (1998)

[文献書誌] Mogi,S.: "Efficient generation of autologous peripheral blood-derived cytotoxic T lymphocytes against poorlyimmunogenic human tumors using recombinant CD80-adenovirous together with interleukin 12 and interleukin 2." Cli.Cancer Res.4. 713-720 (1998)

[文献書誌] Nakajima,A.: "Antitumor effect of CD40 ligand: elicitaton of local and sytemic antitumor responses by IL-I2 and B7" J.Immunol.161. 1901-1907 (1998)

[文献書誌] Judo,S.: "Elevated serum levels of soluble of Fas/APO-1 (CD95) in patients with hepatocellular cartinoma" Clin.Exp.Immunol.112. 166-171 (1998)

[文献書誌] Ogawa,M.: "Multiple roles of IFN-γ in the mediation of IL-I2-induced tumor regression" Cancer Res.58. 2426-2432 (1998)

[文献書誌] Wijesuriya,R.: "B cell-mediated down-reglulation of IFN-γ and IL-I2 production induced during anti-tumor immune responses in the tumor-bearing" Int.Immunol.10. 1057-1065 (1998)

[文献書誌] Ahn,H-J.: "Reguirement for distinct Janus kinases and STAT proteins in T cell proliferation vs IFN-γ production following IL-I2 stimulation" J.Immunol.161. 5893-5900 (1998)

[文献書誌] Ogawa,M.: "A critical role for a peritrumoral stomal reaction in the induction of T cell migration responsible for IL-I2-induced tumor regression" Cancer Res.(In press).

[文献書誌] Fujiwara,H.: "Molecular mechanisms underlying T cell migration responsible for IL-I2-induced tumor regression" Gann Monogr.Cancer Res.(In press).

[文献書誌] Kitamura,H.: "The natural Killer T (NKT) cell ligand α-galactosylceramide demonstrates its immunopotentiating effect by inducing IL-I2..." J.Exp.Med.(In press).

[文献書誌] Yahata,T.: "The essential role of phorbol ester-sensitive protein kinase C isoforms in activation-induced cell death of Th1 cells" Eur.J.Immunol.(In press).

[文献書誌] Sato,M.: "Functional skewing of bone marrow-derived dendritic cells by Th1- or Th2-inducing cytokines" Immunol.Lett.(In press).

[文献書誌] Yahata,T.: "Reconsititution of immune systems in RAG2 -/- mice by transfer with interleukin-l2-induced splenic hematopoietic progenitor cell" Immunol.Lett.62. 165-170 (1998)

[文献書誌] Iwakabe,K.: "The restrain stress derives a shift in Th1/Th2 balance toward Th2-dominant immunity in mice" Immunol.Lett.62. 39-43 (1998)

[文献書誌] Yahata,T.: "Accumulation of IL-I2-activated antitumor effector cells into lymph nodes of tumor-bearing mice" Immunol.Lett.61. 127-133 (1998)

[文献書誌] Oiso,M.: "A newly identified MAGE-3-derived epitope recognized by HLA-A24 restricted cytotoxic T lymphocytes" Int.J.Cancer. (In press).

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

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

[文献書誌] Jiao,Y.: "Sequential T cell response involved in tumor rejection of sarcoma meth A in syngeneic mice" Jpn.J.Cancer Res.89. 657-665 (1998)

1998 年度実績報告書

谷口克千葉大学, 大学院・医学研究所, 教授 (80110310)