Evaluation of molecular and cellular mechanisms of helper T cell-mediated immunity during tumor-rejection

2004 Fiscal Year Final Research Report Summary

• Project/Area Number: 12213003
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Hokkaido University
• Principal Investigator: NISHIMURA Takashi Hokkaido. University, Institute for Genetic Medicine, Professor, 遺伝子病制御研究所, 教授 (30143001)
• Project Period (FY): 2000 – 2004
• Keywords: Helper T cells / Cancer / Th1 / Cancer antigen / Dendritic cells / Gene Therapy / T cell receptor

Research Abstract

The purpose of this project is to evaluate the function of DC subsets and the mechanisms of Th1 /Th2 balance control, which are critical for development of tumor-specific CTL -mediated immunotherapy. We have demonstrated the following evidence. 1. Th1-dominant immunity is critical for activation of Th1 /Tc1 circuit important for tumor-specific immunotherapy. 2. BMDC1, which were induced from bone-marrow cells by culture with GM-CSF, IL-3 and Th1 cytokines, exhibited a potent stimulating activity for inducing allogeneic CTL. Moreover, combination therapy with BM DC1, inactivated tumor and tumor antigen protein caused a complete rejection of tumor tissue. 3. We established a culture method for inducing leukemia-specific CTL from PBMC of leukemia patients. 4. We established the method to prepare gene-modified tumor-specific Th1 cells using tumor-specific TCR genes or Iggene.Especially, it was demonstrated that transfer of class-I-restricted TCR genes into Th1 cells resulted in the generation of functional class-I-restricted Th1 cells. 5. CpG coencapsulated with tumor antigen protein induced tetramer-positive CTL in tumor-bearing mice and cured the mice from tumor. 6. We established a method to prepare Th1 cells, which specifically react to cancer-testis tumor antigen such as NY-ESO-1, MAGE-A4. These Th1 cells are useful to determine helper epitopes of tumor antigen.

Research Products

• [Journal Article] Natural killer cells play a role in MHC class I in vivo induction in tumor cells that are MHC negative in vitro. (2005)
  • Author(s): Kijima, M.
  • Journal Title: Int J Oncol 26 Pages: 679-684
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Natural killer cells play a role in MHC class I in vivo induction in tumor cells that are MHC negative in vitro. (2005)
  • Author(s): Kijima, M., Saio, M., Oyang, G.F., Suwa, T., Miyauchi, R., Kojima, Y., Imai, H., Nakagawa, J., Nonaka, K., Umemura, N., Nishimura, T., Takami, T.
  • Journal Title: Int J Oncol 26 Pages: 679-684
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Liposome-encapsulated CpG oligodeoxynucleotides as a potent adjuvant for inducing type 1 innate immunity. (2004)
  • Author(s): Suzuki, Y.
  • Journal Title: Cancer Res 64 Pages: 8754-8760
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Generation and targeting of human tumor-specific Tc1 and Th1 cells transduced with a lentivirus containing a chimeric immunoglobulin T-cell receptor. (2004)
  • Author(s): Gyobu, H.
  • Journal Title: Cancer Res 64 Pages: 1490-1495
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Potentiation of tumor eradication by adoptive immunotherapy with T-cell receptor gene-transduced T-helper type 1 cells. (2004)
  • Author(s): Chamoto, K.
  • Journal Title: Cancer Res 64 Pages: 386-390
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Generation of leukemia-specific T-helper type 1 cells applicable to human leukemia cell-therapy. (2004)
  • Author(s): Fujimura, T
  • Journal Title: Immunol Lett 93 Pages: 17-25
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The critical role of type-1 innate and acquired immunity in tumor immunotherapy. (2004)
  • Author(s): Ikeda, H.
  • Journal Title: Cancer Sci 95 Pages: 697-703
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Unexpected role of TNF-α in graft versus host reaction (GVHR) : donor-derived TNF-α suppresses GVHR via inhibition of IFN-γ -dependent donor type-1 immunity. (2004)
  • Author(s): Yamamoto, S.
  • Journal Title: Int Immunol, :, 2004 16 Pages: 811-817
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] IFN-γ-induced SOCS-1 regulates STAT6-dependent eotaxin production triggered by IL-4 and TNF-α. (2004)
  • Author(s): Sato, T.
  • Journal Title: Biochem Biophys Res Commun 314 Pages: 468-475
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] STAT6-mediated signaling in Th2-dependent allergic asthma : critical role for the development of eosinophilia, airway hyper-responsiveness and mucus hypersecretion, distinct from its role in Th2 differentiation. (2004)
  • Author(s): Hoshino, A.
  • Journal Title: Int Immunol 16 Pages: 1497-1505
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] NKT cells act as regulatory cells rather than killer cells during activation of NK cell-mediated cytotoxicity by α-galactosylceramide in vivo. (2004)
  • Author(s): Chamoto, K.
  • Journal Title: Immunol Lett 95 Pages: 5-11
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Liposome-encapsulated CpG oligodeoxynucleotides as a potent adjuvant for inducing type 1 innate immunity. (2004)
  • Author(s): Suzuki, Y., Wakita, D., Chamoto, K., Narita, Y., Tsuji, T., Takeshima, T., Gyobu, H., Kawarada, Y., Kondo, S., Akira, S., Katoh, H., Ikeda, H., Nishimura, T.
  • Journal Title: Cancer Res 64 Pages: 8754-8760
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Its possible role inautoimmune diseases (2004)
  • Author(s): Matsuzaki, J., Tsuji, T., Imazeki, I., Ikeda, H., Nishimura, T., Immunosteroid as a regulator for Th1/Th2 balance
  • Journal Title: Autoimmunity (In press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The critical role of type-1 innate and acquired immunity in tumor immunotherapy. (2004)
  • Author(s): Ikeda, H., Chamoto, K., Tsuji, T., Suzuki, Y., Wakita, D., Takeshima, T., Nishimura, T.
  • Journal Title: Cancer Sci 95 Pages: 697-703
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Unexpected role of TNF-a in graft versus host reaction (GVHR) : donor-derived TNF-a suppresses GVHR via inhibition of IFN-y-dependent donor type-1 immunity. (2004)
  • Author(s): Yamamoto, S., Tsuji, T., Matsuzaki, J., Zhange, Y., Chamoto, K., Kosaka, A., Togashi, Y., Sekikawa, K., Sawada, K.I., Takeshima, T., Koike, T., Nishimura, T.
  • Journal Title: Int Immunol 16 Pages: 811-817
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] IFN-y-induced SOCS-1 regulates STAT6-dependent eotaxin production triggered by IL-4 and TNF-a. (2004)
  • Author(s): Sato, T., Saito, R., Jinushi, T., Tsuji, T., Matsuzaki, J., Koda, T., Nishimura, S., Takeshima, H., Nishimura, T.
  • Journal Title: Biochem Biophys Res Commun 314 Pages: 468-475
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] STAT6-mediated signaling in Th2-dependent allergic asthma : critical role for the development of eosinophilia, airway hyper- responsiveness and mucus hypersecretion, distinct from its role in Th2 differentiation. (2004)
  • Author(s): Hoshino, A., Tsuji, T., Matsuzaki, J., Jinushi, T., Ashino, S., Teramura, T., Chamoto, K., Tanaka, Y., Asakura, Y., Sakurai, T., Mita, Y., Takaoka, A., Nakaike, S., Takeshima, T., Ikeda, H., Nishimura, T.
  • Journal Title: Int Immunol 16 Pages: 1497-1505
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Generation and targeting of human tumor-specific Tc1 and Th1 cells transduced with a lentivirus containing a chimeric immunoglobulin T-cell receptor. (2004)
  • Author(s): Gyobu, H., Tsuji, T., Suzuki, Y., Ohkuri, T., Chamoto, K., Kuroki, M., Miyoshi, H., Kawarada, Y., Katoh, H., Takeshima, T., Nishimura, T.
  • Journal Title: Cancer Res 64 Pages: 1490-1495
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Generation of leukemia-specific T-helper type 1 cells applicable to human leukemia cell-therapy. (2004)
  • Author(s): Fujimura, T., Chamoto, K., Tsuji, T., Sato, T., Yokouchi, H., Aiba, S., Tagami, H., Tanaka, J., Imamura, M., Togashi, Y., Koda, T., Nishimura, T.
  • Journal Title: Immunol Lett 93 Pages: 17-25
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Potentiation of tumor eradication by adoptive immunotherapy with T-cell receptor gene-transduced T-helper type 1 cells. (2004)
  • Author(s): Chamoto, K., Tsuji, T., Funamoto, H., Kosaka, A., Matsuzaki, J., Sato, T., Abe, H., Fujio, K., Yamamoto, K., Kitamura, T., Takeshima, T., Togashi, Y., Nishimura, T.
  • Journal Title: Cancer Res 64 Pages: 386-390
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] NKT cells act as regulatory cells rather than killer cells during activation of NK cell-mediated cytotoxicity by α- galactosylceramide in vivo. (2004)
  • Author(s): Chamoto, K., Takeshima, T., Kosaka, A., Tsuji, T., Matsuzaki, J., Togashi, Y., Ikeda, H., Nishimura, T.
  • Journal Title: Immunol Lett 95 Pages: 5-11
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Identification of Th1- and Th2-specific Genes by Microarray Analysis. (2003)
  • Author(s): Li, J.
  • Journal Title: Biomedical Res 24 Pages: 299-307
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] An efficient method to prepare T cell receptor gene-transduced cytotoxic T lymphocytes type 1 applicable to tumor gene cell-therapy. (2003)
  • Author(s): Tsuji, T.
  • Journal Title: Cancer Sci 94 Pages: 389-393
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Functional expression of the TrkC gene, encoding a high affinity recept or for NT-3, in antigen-specific T helper type 2 (Th2) cells. (2003)
  • Author(s): Sekimoto, M.
  • Journal Title: Immunol Lett 88 Pages: 221-226
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] A novel tumor-vaccine cell therapy using bone marrow-derived dendritic cell type 1 and antigen-specific Th1 cells. (2003)
  • Author(s): Sato, M.
  • Journal Title: Int Immunol 15 Pages: 837-843
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Differential regulation of VLA-2 expression on Th1 and Th2 cells : a novel marker for the classification of Th subsets. (2003)
  • Author(s): Sasaki, K
  • Journal Title: Int Immunol 15 Pages: 701-710
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Successful elimination of memory-type CD8+ T cell subsets by the administration of anti-Gr-1 monoclonal antibody in vivo. (2003)
  • Author(s): Matsuzaki, J
  • Journal Title: Cell Immunol 224 Pages: 98-105
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Critical role of the Th1/Tc1 circuit for the generation of tumor-specific CTL during tumor eradication in vivo by Th1-cell therapy. (2003)
  • Author(s): Chamoto, K.
  • Journal Title: Cancer Sci 94 Pages: 924-928
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Identification of Th1-and Th2-specific Genes by Microarray Analysis. (2003)
  • Author(s): Li, J., Koda, T., Yamaguchi, A., Yamamoto, S., Sato, T., Togashi, Y., Nishimura, T.
  • Journal Title: Biomedical Res 24 Pages: 299-307
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] An efficient method to prepare T cell receptor gene-transduced cytotoxic T lymphocytes type 1 applicable to tumor gene cell-therapy. (2003)
  • Author(s): Tsuji, T., Chamoto, K., Funamoto, H., Kosaka, A., Matsuzaki, J., Abe, H., Fujio, K., Yamamoto, K., Kitamura, T., Togashi, Y., Koda, T., Nishimura, T.
  • Journal Title: Cancer Sci 94 Pages: 389-393
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Functional expression of the TrkC gene, encoding a high affinity receptor for NT-3, in antigen-specific T helper type 2 (Th2) cells. (2003)
  • Author(s): Sekimoto, M., Tsuji, T., Matsuzaki, J., Chamoto, K., Koda, T., Nemoto, K., Degawa, M., Nishimura, S., Nishimura, T.
  • Journal Title: Immunol Lett 88 Pages: 221-226
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A novel tumor-vaccine cell therapy using bone marrow-derived dendritic cell type 1 and antigen-specific Th1 cells. (2003)
  • Author(s): Sato, M., Chamoto, K., Nishimura, T.
  • Journal Title: Int Immunol 15 Pages: 837-843
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Differential regulation of VLA-2 expression on Th1 and Th2 cells : a novel marker for the classification of Th subsets. (2003)
  • Author(s): Sasaki, K., Tsuji, T., Jinushi, T., Matsuzaki, J., Sato, T., Chamoto, K., Togashi, Y., Koda, T., Nishimura, T.
  • Journal Title: Int Immunol 15 Pages: 701-710
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Successful elimination of memory-type CD8+T cell subsets by the administration of anti-Gr-1 monoclonal antibody in vivo. (2003)
  • Author(s): Matsuzaki, J., Tsuji, T., Chamoto, K., Takeshima, T., Sendo, F., Nishimura, T.
  • Journal Title: Cell Immunol 224 Pages: 98-105
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Critical role of the Th1/Tc1 circuit for the generation of tumor-specific CTL during tumor eradication in vivo by Th1-cell therapy. (2003)
  • Author(s): Chamoto, K., Kosaka, A., Tsuji, T., Matsuzaki, J., Sato, T., Takeshima, T., Iwakabe, K., Togashi, Y., Koda, T., Nishimura, T.
  • Journal Title: Cancer Sci 94 Pages: 924-928
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Generation of human tumor-specific, HLA class l-restricted Th1 and Tc1 cells by cell engineering with tumor peptide-specific T cell receptor genes.
  • Author(s): Tsuji.T.
  • Journal Title: Blood (In press)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Application of genetically engineered tumor-specific Th1 cells to adoptive tumor immunotherapy.
  • Author(s): Tsuji, T.
  • Journal Title: Annals of Cancer Research and Therapy (In press)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Immunosteroid as a regulator for Th1/Th2 balance : Its possible role inautoimmune diseases
  • Author(s): Matsuzaki, J.
  • Journal Title: Autoimmunity (In press)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Generation of human tumor-specific, HLA class I-restricted Th1 and Tc1 cells by cell engineering with tumor peptide-specific T cell receptor genes.
  • Author(s): Tsuji, T., Yasukawa, M., Matsuzaki, J., Ohkuri, T., Chamoto, K., Wakita, D., Azuma, T., Niiya, H., Miyoshi, H., Kuzushima, K., Oka, Y., Sugiyama, H., Ikeda, H., Nishimura, T.
  • Journal Title: Blood (In press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Application of genetically engineered tumor- specificTh1 cells to adoptive tumor immunotherapy Annals of Cancer Research and Therapy
  • Author(s): Tsuji, T., Chamoto, K., Gyobu, H., Ikeda.H., Nishimura, T.
  • Journal Title: (In press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Book] 分子生物学・免疫学キーワード事典(第2版) (2003)
  • Author(s): 永田和宏
  • Total Pages: 1056
  • Publisher: 医学書院
  • Description: 「研究成果報告書概要(和文)」より
• [Book] 医学大辞典(第1版) (2003)
  • Author(s): 伊藤正男
  • Total Pages: 3088
  • Publisher: 医学書院
  • Description: 「研究成果報告書概要(和文)」より
• [Book] 別冊・医学のあゆみ 細胞免疫療法の現状 (2003)
  • Author(s): 若杉尋
  • Total Pages: 120
  • Publisher: 医歯薬出版株式会社
  • Description: 「研究成果報告書概要(和文)」より
• [Book] 内科学 二分冊版(第2版) (2003)
  • Author(s): 黒川清
  • Total Pages: 2, 580
  • Publisher: 文光堂
  • Description: 「研究成果報告書概要(和文)」より
• [Book] アレルギー病学 (2002)
  • Author(s): 山本一彦
  • Total Pages: 404
  • Publisher: 朝倉書店
  • Description: 「研究成果報告書概要(和文)」より
• [Book] 免疫学辞典(第2版) (2001)
  • Author(s): 大沢利昭
  • Total Pages: 848
  • Publisher: 東京化学同人
  • Description: 「研究成果報告書概要(和文)」より
• [Book] Bio Science新用語ライブラリー免疫第2版 (2000)
  • Author(s): 斉藤隆
  • Publisher: 羊土社
  • Description: 「研究成果報告書概要(和文)」より
• [Patent(Industrial Property Rights)] 改変標的化T細胞の製造方法及び医薬 (2004)
  • Inventor(s): 西村 孝司, 安川 正貴
  • Industrial Property Rights Holder: 北海道ティー・エル・オー株式会
  • Industrial Property Number: 国際出願番号:PCT/JP2004/019714
  • Filing Date: 2004-12-22
  • Description: 「研究成果報告書概要(和文)」より
• [Patent(Industrial Property Rights)] 癌抗原非特異的な標準化T細胞の製造方法及び医薬 (2004)
  • Inventor(s): 西村 孝司
  • Industrial Property Rights Holder: 北海道ティー・エル・オー株式会
  • Industrial Property Number: 特願2004-17740
  • Filing Date: 2004-01-27
  • Description: 「研究成果報告書概要(和文)」より
• [Patent(Industrial Property Rights)] 標的化T細胞の製造方法及び医薬 (2004)
  • Inventor(s): 西村 孝司, 黒木 政秀
  • Industrial Property Rights Holder: 北海道ティー・エル・オー株式会
  • Industrial Property Number: 特願2004-17747
  • Filing Date: 2004-01-27
  • Description: 「研究成果報告書概要(和文)」より
• [Patent(Industrial Property Rights)] ヒトTh1免疫とTh2免疫のバランスを調べるための検査キット (2004)
  • Inventor(s): 西村 孝司
  • Industrial Property Rights Holder: 西村孝司, 東レ株式会社
  • Industrial Property Number: 特願2004-294522
  • Filing Date: 2004-10-07
  • Description: 「研究成果報告書概要(和文)」より
• [Patent(Industrial Property Rights)] 改変標的化T細胞の製造方法及び医薬 (2003)
  • Inventor(s): 西村 孝司, 安川 正貴
  • Industrial Property Rights Holder: 北海道ティー・ェル・ォー株式会社
  • Industrial Property Number: 特願2003-425009
  • Filing Date: 2003-12-22
  • Description: 「研究成果報告書概要(和文)」より
• [Patent(Industrial Property Rights)] ヒトT細胞による肝疾患治療剤 (2002)
  • Inventor(s): 内海 潤, 西村孝司, 富樫 裕二
  • Industrial Property Rights Holder: 東レ株式会社
  • Industrial Property Number: 特願2002-130032
  • Filing Date: 2002-05-01
  • Description: 「研究成果報告書概要(和文)」より
• [Patent(Industrial Property Rights)] 免疫調節作用関連の新規遺伝子及びTh1ヘルパーT細胞とTh2ヘルパーT細胞のバランスを調べる検査方法 (2002)
  • Inventor(s): 西村 孝司
  • Industrial Property Rights Holder: 西村 孝司, 東レ株式会社
  • Industrial Property Number: 特願2002-314957
  • Filing Date: 2002-10-29
  • Description: 「研究成果報告書概要(和文)」より
• [Patent(Industrial Property Rights)] 抗原特異的ヒトT細胞の製造方法及び医薬 (2001)
  • Inventor(s): 西村 孝司, 内海 潤
  • Industrial Property Rights Holder: 東レ株式会社, 西村 孝司
  • Industrial Property Number: 特願2001-255095, (識別番号501335575)
  • Filing Date: 2001-08-28
  • Description: 「研究成果報告書概要(和文)」より
• [Patent(Industrial Property Rights)] 免疫賦活剤 (2000)
  • Inventor(s): 田中 善孝, 渡辺 一仁, 西村 孝司
  • Industrial Property Rights Holder: 大正製薬株式会社, 学校法人東海大学
  • Patent Publication Number: 特開2000-281571 (P2000-281571A)
  • Acquisition Date: 2000-10-10
  • Description: 「研究成果報告書概要(和文)」より
• [Patent(Industrial Property Rights)] ガン免疫賦活剤およびアレルギー免疫抑制剤 (2000)
  • Inventor(s): 西村 孝司, 佐藤 まりも, 水谷 武雄, 古家 健二
  • Industrial Property Rights Holder: 三井製糖株式会社
  • Patent Publication Number: 特開2000-297045 (P 2000-297045A)
  • Acquisition Date: 2000-10-24
  • Description: 「研究成果報告書概要(和文)」より