The development of immuno-modulation therapy by use of ES cell-derived dendritic cells

• Project/Area Number: 16590988
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: 膠原病・アレルギー・感染症内科学
• Research Institution: Kumamoto University
• Principal Investigator: SENJU Satoru KUMAMOTO UNIV., GRAD.SCHL.MED.SCIENCES, ASSOCIATE PROFESSOR, 大学院・医学薬学研究部, 助教授 (50274709)
• Co-Investigator(Kenkyū-buntansha): NISHIMURA Yasuharu KUMAMOTO UNIV., GRAD.SCHL.MED.SCIENCES, PROFESSOR, 大学院・医学薬学研究部, 教授 (10156119) ; IRIE Atsushi KUMAMOTO UNIV., GRAD.SCHL.MED.SCIENCES, ASSOCIATE, 大学院・医学薬学研究部, 助手 (30250343) ; NAKATSURA Tetsuya KUMAMOTO UNIV., GRAD.SCHL.MED.SCIENCES, ASSOCIATE, 大学院・医学薬学研究部, 助手 (30343354)
• Project Period (FY): 2004 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥3,600,000 (Direct Cost: ¥3,600,000); Fiscal Year 2005: ¥1,400,000 (Direct Cost: ¥1,400,000); Fiscal Year 2004: ¥2,200,000 (Direct Cost: ¥2,200,000)
• Keywords: ES cells / dendritic cells / immunity / anti-tumor immunotherapy / chemokine / autoimmune disease / MHC / 胚性幹細胞 / 免疫応答 / 免疫寛容 / 再生医療 / 臓器移植 / MHC / 遺伝子導入 / 実験的自己免疫性脳脊髄炎 / 免疫制御性T細胞 / T細胞

Research Abstract

In the previous study, we developed a method to generate dendritic cells (DC) from mouse embryonic stem (ES) cells (ES-DC). Genetic modification of ES-DC can readily be done by transfection of ES cells and subsequent their differentiation to DC. In this research period, we carried out the following projects.
Anti-tumor immunotherapy by ES-DC
Immunization with DC expressing antigen plus T cell-attracting chemokines provided protection from antigen-expressing tumor cells more potently than that with antigen only. We demonstrated that anti-tumor immunotherapy with ES-DC was effective even in the allogeneic recipient mice, if some of MHC alleles were shared by the ES-DC and the mice. ES-DC expressing Glypican-3, a recently identified oncofetal antigen, induced protective immunity against highly metastatic mouse melanoma, B16-F10.
Antigen-specific down-modulation of immune response by ES-DC
We tried to establish a method for antigen-specific down-modulation of immune response by ES-DC expressing antigen along with immuno-suppressive molecules. We demonstrated that severity of myelin oligodendrocyte glycoprotein (MOG) peptide-induced experimental autoimmune encephalomyelitis (EAE) was reduced in mice treated with the double-transfectant ES-DC, presenting myelin oligodendrocyte glycoprotein (MOG) peptide in the context of MHC class II molecules and simultaneously expressing TNF-related apoptosis-inducing ligand (TRAIL) or Programmed Death-1 ligand (PD-L1). In addition, we obtained several lines of evidence showing that regulatory T cells were involved in the disease-preventive effect induced by ES-DC expressing TRAIL.
Generation of ES-DC form primate ES cells
For future clinical applications of this technology, it is necessary to develop a method to generate DC from human ES cells. Before we use human ES cells, we established a method to generate ES-DC from a cynomolgus monkey ES cell line, which is similar in many aspects to human ES cells.

Research Products

• [Journal Article] Embryonic stem cell-derived dendritic cells expressing Glypican-3, a recently identified oncofetal antigen, induce protective immunity against highly metastatic mouse melanoma, B16-F10. (2006)
  • Author(s): Motomura.Y.et al.
  • Journal Title: Cancer Research 66 Pages: 2414-2422
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Embryonic stem cell-derived dendritic cells expressing Glypican-3, a recently identified oncofetal antigen, induce protective immunity against highly metastatic mouse melanoma, B16-F10. (2006)
  • Author(s): Motomura, Y., Senju, S., Nakatsura, T., Matsuyoshi, H., Hirata, S., Monji, M., Komori, H., Fukuma, D., Baba, H., Nishimura, Y.
  • Journal Title: Cancer Research 66 Pages: 2414-2422
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Embryonic stem cell-derived dendritic cells expressing Glypican-3, a recently identified oncofetal antigen, induce protective immunity against highly metastatic mouse melanoma, B16-F10. (2006)
  • Author(s): Motomura, Y. et al.
  • Journal Title: Cancer Research 66 Pages: 2414-2422
• [Journal Article] Prevention of experimental autoimmune encephalomyelitis by transfer of ES cell-derived dendritic cells expressing MOG peptide along with TRAIL or PD-LI. (2005)
  • Author(s): Hirata, S. et al.
  • Journal Title: J. Immunol. 174 Pages: 1888-1897
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Cancer prevention with semi-allogeneic ES cell-derived dendritic cells. (2005)
  • Author(s): Fukuma, D. et al.
  • Journal Title: Biochem. Biophys. Res. Comm. 335 Pages: 5-13
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] DNA vaccination of HSP105 leads to tumor rejection of colorectal cancer and melanoma in mice through activation of both CD4^+T cells and CD8^+T cells. (2005)
  • Author(s): Miyazaki, M. et al.
  • Journal Title: Cancer Science 96 Pages: 695-705
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Therapeutic effect of a-galactosylceramide-loaded dendritic cells genetically engineered to express SLC/CCL21 along with tumor antigen against peritoneally disseminated tumor cells. (2005)
  • Author(s): Matsuyoshi, H. et al.
  • Journal Title: Cancer Science 96 Pages: 889-896
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Direct recognition and lysis of leukemia cells by WT1-specific CD4^+T lymphocytes in an HLA class II-restricted manner. (2005)
  • Author(s): Guo, Y.et al.
  • Journal Title: Blood 106 Pages: 1415-1418
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 樹状細胞の移入による免疫抑制療法 (2005)
  • Author(s): 平田真哉, 千住 覚, 西村泰治
  • Journal Title: 臨床免疫 43(5) Pages: 603-607
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 抗原提示細胞をターゲットとした免疫抑制法 (2005)
  • Author(s): 平田真哉, 千住 覚, 西村泰治
  • Journal Title: 分子リウマチ 2(1) Pages: 47-54
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] HLA不適合と拒絶反応 (2005)
  • Author(s): 松吉秀武, 千住 覚, 門司幹男, 西村泰治
  • Journal Title: 臨床免疫学(上) 63(4) Pages: 621-631
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Prevention of experimental autoimmune encephalomyelitis by transfer of ES cell-derived dendritic cells expressing MOG peptide along with TRAIL or PD-L1. (2005)
  • Author(s): Hirata, S., Senju, S., Matsuyoshi, H., Fukuma, D., Uemura, Y., Nishimura, Y.
  • Journal Title: J.Immunol. 174 Pages: 1888-1897
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Cancer prevention with semi-allogeneic ES cell-derived dendritic cells. (2005)
  • Author(s): Fukuma, D., Matsuyoshi, H., Hirata, S., Kurisaki, A., Yoshitake, Y., Sinohara, M., Nishimura, Y., Senju, S.
  • Journal Title: Biochem.Biophys.Res.Comm. 335 Pages: 5-13
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] DNA vaccination of HSP105 leads to tumor rejection of colorectal cancer and melanoma in mice through activation of both CD4^+T cells and CD8^+ T cells. (2005)
  • Author(s): Miyazaki, M.^*, Nakatsura, T.^*, Senju, S., Monji, M., Hosaka, S., Komori, H., Yoshitake, Y., Motomura, Y., Yokomine, K., Minohara, M., Kubo, T., Ishihara, K., Hatayama, T., Ogawa, M., Nishimura, Y.(^*equal contribution)
  • Journal Title: Cancer Science 96 Pages: 695-705
  • NAID: 10017091223
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Therapeutic effect of a-galactosylceramide-loaded dendritic cells genetically engineered to express SLC/CCL21 along with tumor antigen against peritoneally disseminated tumor cells. (2005)
  • Author(s): Matsuyoshi, H., Hirata, S., Yoshitake, Y., Motomura, Y., Fukuma, D., Kurisaki, A., Nakatsura, T., Nishimura, Y., Senju, S.
  • Journal Title: Cancer Science 96 Pages: 889-896
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Direct recognition and lysis of leukemia cells by WT1-specific CD4^+T lymphocytes in an HLA class II-restricted manner. (2005)
  • Author(s): Guo, Y., Niiya, H., Azuma, T., Uchida, N., Yakushijin Y., Sakai, I., Hato, T., Takahashi, M., Senju, S., Nishimura, Y., Yasukawa M.
  • Journal Title: Blood 106 Pages: 1415-1418
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Prevention of experimental autoimmune encephalomyelitis by transfer of ES cell-derived dendritic cells expressing MOG peptide along with TRAIL or PD-L1. (2005)
  • Author(s): Hirata, S. et al.
  • Journal Title: J.Immunol. 174 Pages: 1888-1897
• [Journal Article] Anti-cancer immunotherapy with semi-allogeneic embryonic stem cell-derived dendritic cells genetically engineered to express a model tumor antigen. (2005)
  • Author(s): Fukuma, D. et al.
  • Journal Title: Biochem.Biophys.Res.Comm. 335 Pages: 5-13
• [Journal Article] DNA vaccination of HSP105 leads to tumor rejection of colorectal cancer and melanoma in mice through activation of both CD4^+ and CD8^+ T cells. (2005)
  • Author(s): Miyazaki, M. et al.
  • Journal Title: Cancer Science 96 Pages: 695-705
• [Journal Article] Direct recognition and lysis of leukemia cells by WT1-specific CD4^+ T lymphocytes in an HLA class II-restricted manner. (2005)
  • Author(s): Guo, Y.et al.
  • Journal Title: Blood 106 Pages: 1415-1418
• [Journal Article] 樹状細胞の移入による免疫抑制療法 (2005)
  • Author(s): 平田真哉, 千住覚, 西村泰治
  • Journal Title: 臨床免疫 43(5) Pages: 603-607
• [Journal Article] 抗原提示細胞をターゲットとした免疫抑制法 (2005)
  • Author(s): 平田真哉, 千住覚, 西村泰治
  • Journal Title: 分子リウマチ 2(1) Pages: 47-54
• [Journal Article] Prevention of experimental autoimmune encephalomyelitis by transfer of EScell-derived dendritic cells expressing MOG peptide along with TRAIL or PD-1. (2005)
  • Author(s): Hirata, S.et al.
  • Journal Title: J.Immunol. 174 Pages: 1888-1897
• [Journal Article] 抗原提示細胞をターゲットとした免疫抑制療法 (2005)
  • Author(s): 平田真哉, 千住覚, 西村泰治
  • Journal Title: 分子リウマチ 2・1 Pages: 47-54
• [Journal Article] Mouse homologue of a nobel human oncofetal antigen, Glypican-3, evokes T cell-mediated tumor rejection without autoimmune reactions in mice. (2004)
  • Author(s): Nakatsura, T. et al.
  • Journal Title: Clin. Cancer Res 10 Pages: 8630-8640
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Identification of glypican-3 as a novel tumor marker for melanoma. (2004)
  • Author(s): Nakatsura, T. et al.
  • Journal Title: Clin. Cancer Res 10 Pages: 6612-6621
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Proliferation potential-related protein, an ideal esophageal cancer antigen for immnotherapy, identified using complementary DNA microarray analysis. (2004)
  • Author(s): Yoshitake, Y. et al.
  • Journal Title: Clin. Cancer Res. 10 Pages: 6437-6448
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Identification of a novel human cancer/testis antigen, KM-HN-1, recognized by cellular and humoral immune responses. (2004)
  • Author(s): Monji, M. et al.
  • Journal Title: Clin. Cancer Res. 10 Pages: 6047-6057
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Detection of the novel autoantibody (anti-UACA antibody) in patients with Graves disease. (2004)
  • Author(s): Ohkura, T. et al.
  • Journal Title: Biochem. Biophys. Res. Comm. 321 Pages: 432-440
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 抗原とケモカインを共発現させたES細胞由来の樹状細胞を用いた抗腫瘍免疫療法 (2004)
  • Author(s): 松吉秀武, 千住 覚, 西村泰治
  • Journal Title: 臨床免疫 42(1) Pages: 110-114
  • NAID: 80016807917
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] ES細胞由来の樹状細胞による免疫制御 (2004)
  • Author(s): 松吉秀武, 千住 覚, 西村泰治
  • Journal Title: 感染、炎症、免疫-連載 : ビジュアルデビュー 34(2) Pages: 32-39
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 抗原提示細胞をターゲットとした免疫抑制法 (2004)
  • Author(s): 平田真哉, 千住 覚, 西村泰治
  • Journal Title: Mebio 21(10) Pages: 33-41
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Mouse homologue of a novel human oncofetal antigen, Glypican-3, evokes T cell-mediated tumor rejection without autoimmune reactions in mice. (2004)
  • Author(s): Nakatsura, T., Komori, H., Kubo, T., Yoshitake, Y., Senju, S., Katagiri, T., Furukawa, Y., Oagawa, M., Nakamura, Y., Nishimura, Y.
  • Journal Title: Clin.Cancer Res 10 Pages: 8630-8640
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Identification of glypican-3 as a novel tumor marker for melanoma. (2004)
  • Author(s): Nakatsura, T., Kageshita, T., Ito, S., Wakamatsu, K., Monji, M., Ikuta, Y., Senju, S., Ono, T., Nishimura, Y.
  • Journal Title: Clin.Cancer Res. 10 Pages: 6612-6621
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Proliferation potential-related protein, an ideal esophageal cancer antigen for immnotherapy, identified using complementary DNA microarray analysis. (2004)
  • Author(s): Yoshitake, Y., Nakatsura, T., Monji, M., Senju, S., Matsuyoshi, H., Tsukamoto, H., Hosaka, S., Komori, H., Fukuma, D., Ikuta, Y., Katagiri, T., Furukawa, Y., Ito, H., Shinohara, M., Nakamura, Y., Nishimura, Y.
  • Journal Title: Clin.Cancer Res. 10 Pages: 6437-6448
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Identification of a novel human cancer/testis antigen, KM-HN-1, recognized by cellular and humeral immune responses. (2004)
  • Author(s): Monji, M., Nakatsura, T., Senju, S., Yoshitake, Y., Sawatsubashi, M., Shinohara, M., Kageshita, T., Ono, T., Inokuchi, A., Nishimura, Y.
  • Journal Title: Clin.Cancer Res. 10 Pages: 6047-6057
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Detection of the novel autoantibody (anti-UACA antibody) in patients with Graves disease. (2004)
  • Author(s): Ohkura, T., Taniguchi, S., Yamada, K., Nishio, N., Okamura, T., Yoshida, A., Kamijou, K., Fukata, S., Kuma, K., Inoue, Y., Hisatome, I., Senju, S., Nishimura Y., Shigemasa, C.
  • Journal Title: Biochem.Biophys.Res.Comm. 321 Pages: 432-440
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Mouse homologue of a novel human oncofetal antigen, Glypican-3, evokes T cell-mediated tumor rejection without autoimmune reactions in mice. (2004)
  • Author(s): Nakatsura, T.et al.
  • Journal Title: Clin.Cancer Res. 10 Pages: 8630-8640
• [Journal Article] Identification of glypican-3 as a novel tumor marker for melanoma. (2004)
  • Author(s): Nakatsura, T.et al.
  • Journal Title: Clin.Cancer Res. 10 Pages: 6612-6621
• [Journal Article] Proliferation potential-related protein, an ideal esophageal cancer antigen forimmnotherapy, identified using complementary DNA microarray analysis. (2004)
  • Author(s): Yoshitake, Y.et al.
  • Journal Title: Clin.Cancer Res. 10 Pages: 6437-6448
• [Journal Article] Identification of a novel human cancer/testis antigen, KM-HN-1, recognized by cellular and humoral immune responses. (2004)
  • Author(s): Monji, M.et al.
  • Journal Title: Clin.Cancer Res. 10 Pages: 6047-6057
• [Journal Article] Detection of the novel autoantibody (anti-UACA antibody) in patients with Graves disease. (2004)
  • Author(s): Ohkura, T.et al.
  • Journal Title: Biochem.Biophys.Res.Comm. 321 Pages: 432-440
• [Journal Article] Enhanced priming of antigen-specific CTL in vivo by transfer of ES cell-derived dendritic cells expressing chemokine along with antigenic protein ; application to anti-tumor vaccination. (2004)
  • Author(s): Matsuyoshi, H.et al.
  • Journal Title: J.Immunol. 172 Pages: 776-786
• [Journal Article] ES細胞由来の樹状細胞による免疫制御 (2004)
  • Author(s): 松吉秀武, 千住 覚, 西村泰治
  • Journal Title: 感染、炎症、免疫-連載:ビジュアルデビュー 34・2 Pages: 32-39
• [Journal Article] 抗原とケモカインを共発現させたES細胞由来の樹状細胞を用いた抗腫瘍免疫療法 (2004)
  • Author(s): 松吉秀武, 千住 覚, 西村泰治
  • Journal Title: 臨床免疫 42・1 Pages: 110-114
  • NAID: 80016807917
• [Journal Article] 抗原提示細胞をターゲットとした免疫抑制法 (2004)
  • Author(s): 平田真哉, 千住覚, 西村泰治
  • Journal Title: Mebio 21・10 Pages: 33-41
• [Patent(Industrial Property Rights)] 霊長類動胚性幹細胞から樹状細胞の製造方法 (2004)
  • Inventor(s): 千住覚, 西村泰治
  • Industrial Property Rights Holder: 千住覚, 田辺製薬株式会社
  • Industrial Property Number: 2004-249062
  • Filing Date: 2004-08-27
  • Description: 「研究成果報告書概要(和文)」より
• [Patent(Industrial Property Rights)] 霊長類動物胚性幹細胞から樹状細胞の製造方法 (2004)
  • Inventor(s): 千住 覚, 西村 泰治
  • Industrial Property Rights Holder: 千住 覚, 田辺製薬株式会社
  • Filing Date: 2004-08-27