1996 Fiscal Year Annual Research Report

ヒト自家癌拒絶の免疫学的分子機構

Research Project

Project/Area Number	08266111
Research Institution	Sapporo Medical University
Principal Investigator	菊地浩吉札幌医科大学, 医学部, 教授 (00045345)
Co-Investigator(Kenkyū-buntansha)	松浦晃洋札幌医科大学, 医学部, 助教授 (70157238) 古川圭子三重大学, 医学部, 助手 (50260732) 益子高東北大学, 薬学部, 助教授 (30157200) 別宮好文東京医科学研究所, 助手 (70199454) 笠原正典北海道大学, 医学部, 助教授 (30241318)
Keywords	人癌特異抗原 / 自家癌 / キラーT細胞クローン / T細胞抗原レセプター / 胃癌抗原 / 原癌遺伝子 / イムノプロテアソーム / 癌関連糖鎖
Research Abstract	癌の特異的免疫治療を目指し、人癌特異抗原を同定し、その自家T細胞による免疫学的認識、拒絶の分子機構を明らかにし自家癌拒絶の誘導法の開発を試みた。 1.癌患者リンパ球から、自家胃癌、膵癌、口腔癌特異的キラーT細胞クローンおよびヘルパーT細胞クローンを樹立し、癌抗原提示分子が各々、HLA-A31、-A24、-DR^*08032であることを証明した。自家胃癌に対するCTL誘導能を有する結合ペプチドの画分を精製し、抗原ペプチド分子の同定に成功した。 2.ヒト胃癌、膵癌を特異的に障害するT細胞クローンの抗原レセプター遺伝子をT細胞株にトランスフェクトし、TCR分子の細胞表面発現を認め、更にこれが自家癌抗原を認識することを確かめた。 3.原癌遺伝子(C-erbB-2)産物のKd拘束性ペプチド感作により特異的CTLを誘導できた。 4.MC誘発肉腫CMS5に特異的なCTLcloneの認識する腫瘍抗原遺伝子を単離し、その産物が第136アミノ酸にK→Q変異を持つ変異型MAPkinase(ERK2)であることを明らかにした。 5.イムノプロテアソームβサブユニット・ペアをコードする遺伝子を単離し、その構造、染色体居在を明らかにした。 6.腫瘍細胞の臓器浸潤や血行性転位に関与する癌関連糖鎖を合成する糖転位酵素、シアリルトランスフェラーゼおよびフコシルトランスフェラーゼの発現をアンチセンスcDNA等を用い制御できることを、成人T細胞性白血病および大腸癌について示した。 7.2つのヒトメラノーマ特異的CTLクローンは、HLA-A2拘束性にメラノーマを認識し、同時にHLA非拘束性に一部のメラノーマ細胞に対して細胞傷害活性を示した。これらの2つの異なった認識は1つのTCRによってなされていることが明らかになった。

Research Products
(18 results)

All Other

All Publications (18 results)

[Publications] Tamura,Y.,Kikuchi,K.他: "Inhibition of natural killer cell cytotoxicity by cell growth-related molecules." Jpn.J.Cancer Res.87. 623-630
[Publications] Kamiguchi,K.,Kikuchi,K.他: "Non-MHC class I regulatory molecule for the cytotoxicity by natural killer cells." Art.Organs. 20. 862-865
[Publications] Yasoshima,T.,Kikuchi,K.他: "Estabilishment and characterization of human gastric carcinoma lines with high metastatic potential in the liver. Changes in integrin expression associated with the ability to metastasize in the liver of nude mice." Jpn.J.Cancer Res.87. 153-160
[Publications] Takashima,S.,Kikuchi,K.他: "Interaction between cell-surface-expressed 70-kilodalton heat shock protein-like antigen and CD3^+4^-8^- killer T cells." Artificial Organs. 20. 857-861
[Publications] Yasoshima,T.,Kikuchi,K.他: "Changes in adhesion molecules expression associating with the ability of human gastric cancer cells to metastasize in the liver. In Tahara,E.,Sugimachi,K.and Oophara,T.Eds.,Recent Advances in Gastroenterological Carcinogenesis I,P."
[Publications] Kasahara,M.,Ishibashi,T.他: "Chromosomal localization of the mouse proteasome Z subunit gene reveals an ancient chromosomal duplication involving the major histocompatibility complex." Proc.Natl.Acad.Sci.U.S.A.93. 9096-9101
[Publications] Kandil,E.,Kasahara,M.他: "Isolation of low molecular mass polypeptide complementary DNA clones from primitive vertebrates : Implications for the origin of MHC class I-restricted antigen presentation." J.Immunol.156. 4245-4253
[Publications] Kasahara,M.,Flajnik,M.F.他: "Origin and evolution of the class I gene family : Why are some of the mammalian class I genes encoded outside the major histocompatibility complex?" Res.Immunol.147. 278-284
[Publications] Hayashi,M.,Kasahara,M.他: "Characterization of a human glycoprotein with a potential role in sperm-egg fusion : cDNA cloning,immunohistochemical localization,and chromosomal assignment of the gene (AEGL1)." Genomics. 32. 367-374
[Publications] Beck,Y.,Takiguchi,M.他: "Dual recognition of a human cytotoxic T cell clone for melanoma antigens." Cancer Res.56. 2368-2374
[Publications] Masuko,T.and Takeuchi,H.他: "Lipid structure of cytotoxic granules in living human killer Tlymphocytes studied by raman microspectoscopy. Biochim.Biophys." Acta in press.
[Publications] Furukawa,K.,Aizawa,S.他: "Mice with disrupted GM2/GD2 synthase gene lack complex gangliosides,but exhibit only subtle defects in their nervous system." Proc.Natl.Acad.Sci.USA. 93. 10662-10667
[Publications] Furukawa,K.他: "Genomic organization and chromosomal assignment of the human β1,4-N-acetylgalactosaminyltransferase gene : Identification of multipletranscription units." J.Biol.Chem.271. 20836-20844
[Publications] Furukawa,K,,他: "High expression of ganglioside GD3 synthase gene in adult T cell leukemia cells unrelated to the gene expression of human T lymphotropic virus type I." Cancer Res.56. 2844-2848
[Publications] Tsuyuoka,K.,and Kannagi,R.他: "Characterization of a T-Cell line specific to an anti-Id antibody related to the carbohydrate antigen,sialyl SSEA-1,and the immunodominat T-Cell antigenic site of the antibody." J.Immunol.157. 661-669
[Publications] Narita,T.,Kannagi,R.他: "Alteration of integrins by heparin-binding EGF-like growth factor (HB-EGF) in human breast cancer cells." Oncology. 53. 374-381
[Publications] Matsuura,A.,Kikuchi,K.他: "Clonal dominance of human autologous cytotoxic T lymphocytes against gastic carcinoma : Molecular stability of complimentarity determining region-3 structure of T cell receptor α/β gene." Int.Immunol.8. 75-82
[Publications] Matsuura,A.,Fujimoto,J.他: "Inhibition of resistance to hemopoietic allografts in G-CSF transgenic mice." Eur.J.Immunol.26. 115-119

1996 Fiscal Year Annual Research Report

ヒト自家癌拒絶の免疫学的分子機構

Principal Investigator

菊地 浩吉 札幌医科大学, 医学部, 教授 (00045345)

Research Products

[Publications] Tamura,Y.,Kikuchi,K.他: "Inhibition of natural killer cell cytotoxicity by cell growth-related molecules." Jpn.J.Cancer Res.87. 623-630

[Publications] Kamiguchi,K.,Kikuchi,K.他: "Non-MHC class I regulatory molecule for the cytotoxicity by natural killer cells." Art.Organs. 20. 862-865

[Publications] Yasoshima,T.,Kikuchi,K.他: "Estabilishment and characterization of human gastric carcinoma lines with high metastatic potential in the liver. Changes in integrin expression associated with the ability to metastasize in the liver of nude mice." Jpn.J.Cancer Res.87. 153-160

[Publications] Takashima,S.,Kikuchi,K.他: "Interaction between cell-surface-expressed 70-kilodalton heat shock protein-like antigen and CD3^+4^-8^- killer T cells." Artificial Organs. 20. 857-861

[Publications] Yasoshima,T.,Kikuchi,K.他: "Changes in adhesion molecules expression associating with the ability of human gastric cancer cells to metastasize in the liver. In Tahara,E.,Sugimachi,K.and Oophara,T.Eds.,Recent Advances in Gastroenterological Carcinogenesis I,P."

[Publications] Kasahara,M.,Ishibashi,T.他: "Chromosomal localization of the mouse proteasome Z subunit gene reveals an ancient chromosomal duplication involving the major histocompatibility complex." Proc.Natl.Acad.Sci.U.S.A.93. 9096-9101

[Publications] Kandil,E.,Kasahara,M.他: "Isolation of low molecular mass polypeptide complementary DNA clones from primitive vertebrates : Implications for the origin of MHC class I-restricted antigen presentation." J.Immunol.156. 4245-4253

[Publications] Kasahara,M.,Flajnik,M.F.他: "Origin and evolution of the class I gene family : Why are some of the mammalian class I genes encoded outside the major histocompatibility complex?" Res.Immunol.147. 278-284

[Publications] Hayashi,M.,Kasahara,M.他: "Characterization of a human glycoprotein with a potential role in sperm-egg fusion : cDNA cloning,immunohistochemical localization,and chromosomal assignment of the gene (AEGL1)." Genomics. 32. 367-374

[Publications] Beck,Y.,Takiguchi,M.他: "Dual recognition of a human cytotoxic T cell clone for melanoma antigens." Cancer Res.56. 2368-2374

[Publications] Masuko,T.and Takeuchi,H.他: "Lipid structure of cytotoxic granules in living human killer Tlymphocytes studied by raman microspectoscopy. Biochim.Biophys." Acta in press.

[Publications] Furukawa,K.,Aizawa,S.他: "Mice with disrupted GM2/GD2 synthase gene lack complex gangliosides,but exhibit only subtle defects in their nervous system." Proc.Natl.Acad.Sci.USA. 93. 10662-10667

[Publications] Furukawa,K.他: "Genomic organization and chromosomal assignment of the human β1,4-N-acetylgalactosaminyltransferase gene : Identification of multipletranscription units." J.Biol.Chem.271. 20836-20844

[Publications] Furukawa,K,,他: "High expression of ganglioside GD3 synthase gene in adult T cell leukemia cells unrelated to the gene expression of human T lymphotropic virus type I." Cancer Res.56. 2844-2848

[Publications] Tsuyuoka,K.,and Kannagi,R.他: "Characterization of a T-Cell line specific to an anti-Id antibody related to the carbohydrate antigen,sialyl SSEA-1,and the immunodominat T-Cell antigenic site of the antibody." J.Immunol.157. 661-669

[Publications] Narita,T.,Kannagi,R.他: "Alteration of integrins by heparin-binding EGF-like growth factor (HB-EGF) in human breast cancer cells." Oncology. 53. 374-381

[Publications] Matsuura,A.,Kikuchi,K.他: "Clonal dominance of human autologous cytotoxic T lymphocytes against gastic carcinoma : Molecular stability of complimentarity determining region-3 structure of T cell receptor α/β gene." Int.Immunol.8. 75-82

[Publications] Matsuura,A.,Fujimoto,J.他: "Inhibition of resistance to hemopoietic allografts in G-CSF transgenic mice." Eur.J.Immunol.26. 115-119

菊地浩吉札幌医科大学, 医学部, 教授 (00045345)