2003 Fiscal Year Final Research Report Summary
Antigen-specific immune-regulation by genetically modified ES cell-derived dendritic cells
| Project/Area Number |
14570421
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
内科学一般
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| Research Institution | Kumamoto University |
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Principal Investigator |
SENJU Satoru KUMAMOTO UNIVERSITY, GRAD.SCHL.MED.SCIENCES, ASSOCIATE PROFESSOR, 大学院・医学薬学研究部, 講師 (50274709)
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| Co-Investigator(Kenkyū-buntansha) |
NISHIMURA Yasuharu KUMAMOTO UNIVERSITY, GRAD.SCHL.MED.SCIENCES, PROFESSOR, 大学院・医学薬学研究部, 教授 (10156119)
IRIE Atsushi KUMAMOTO UNIVERSITY, GRAD.SCHL.MED.SCIENCES, RES.ASSOCIATE, 大学院・医学薬学研究部, 助手 (30250343)
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| Project Period (FY) |
2002 – 2003
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| Keywords | T cell / MHC / chemokine / embryonic stem cell / dendritic cell / tumor immunology / autoimmune diseases / EAE |
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| Research Abstract |
We developed a method to generate dendritic cells (DC) from mouse embryonic stem (ES) cells. We cultured ES cells for 10 days on feeder cell layer of OP9 in the presence of GM-CSF in the latter 5 days. The resultant ES cell-derived floating cells were cultured without feeder cells in culture medium containing GM-CSF. In about 7 days, irregularly shaped floating cells with protrusions appeared and they expressed MHC class II, CD11c, CD80, and CD86. They had capacity to stimulate allogeneic MLR and to process and present protein antigen to T cells. We designated them ES-DCs, and the functions were comparable to those of DC generated from bone marrow cells. Genetic modification of ES-DC can readily be done by transfection of ES cells and subsequent their differentiation to DC. ES-DC introduced with an invariant chain-based epitope-presenting vector presented a PCC epitope in the context of MHC class II molecules very efficiently in vitro. We primed OVA-specific cytotoxic T lymphocytes by
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injecting mice with ES-DC introduced with an OVA-expression vector, demonstrating immunization with ES-DC genetically engineered to express antigen. To improve the capacity of ES-DC to prime T cells in vivo, we generated double-transfectant ES-DC expressing a chemokine along with OVA. Immunization with DC expressing OVA plus SLC or Mig provided protection from OVA-expressing tumor cells more potently than that with OVA only. Severity of myelin oligodendrocyte glycoprotein (MOG) peptide-induced experimental autoimmune encephalomyelitis (EAE) was significantly 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). Antigen-specific imnmuno-modulation by transfer of double-transfectant ES-DC presenting antigen and simultaneously expressing immune-regulatory molecules would be realized in the future as a medical technology. Less
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[Publications] Nakatsura, T., Kageshita, T., Ito, S., Wakamatsu, K., Monji, M., Ikuta, Y., Senju, S., Ono, T., Nishimura, Y.: "Identification of glypican-3 as a novel tumor marker for melanoma."Clinical Cancer Research. (in press).
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「研究成果報告書概要(欧文)」より
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[Publications] Matsuyoshi, H., Senju, S., Hirata, S., Yoshitake, Y., Uemura, Y., Nishimura, Y.: "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."J.Immunol.. 172. 776-786 (2004)
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[Publications] Senju, S., Hirata, S., Matsuyoshi, H., Masuda, M., Uemura, Y., Araki, K., Yamamura, K-I., Nishimura, Y.: "Generation and genetic modification of dendritic cells derived from mouse embryonic stem cells."Blood. 101. 3501-3508 (2003)
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「研究成果報告書概要(欧文)」より
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[Publications] Uemura, Y., Senju, S., Maenaka, K., Iwai, L.K., Fujii, S., Tabata, H., Tsukamoto, H., Hirata, S., Chen, Y-Z, Nishimura, Y.: "Systematic analysis of the combinatorial nature of epitopes recognized by TCR leads to identification of mimicry epitopes for GAD65 specific TCRs"J.Immunol.. 170. 947-960 (2003)
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[Publications] Kobayashi, H., Omiya, R., Sodey, B., Yanai, M., Oikawa, K., Sato, K., Kimura, S., Senju, S., Nishimura, Y., Tateno, M., Celis, E.: "Identification of Naturally Processed Helper T-Cell Epitopes from Prostate-Specific Membrane Antigen Using Peptide-Based in Vitro Stimulation"Clinical Cancer Research. 9. 5386-5393 (2003)
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「研究成果報告書概要(欧文)」より
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[Publications] Nakatsura, T., Yoshitake, Y., Senju, S., Monji, M., Komori, H., Motomura, Y., Hosaka, S., Beppu, T., Ishiko, T., Kamohara, H., Ashihara, H., Katagiri, T., Furukawa, Y., Fujiyama, S., Ogawa, M., Nakamura, Y., Nishimura, Y.: "Glypican-3, overexpressed specifically in human hepatocellular carcinoma, is a novel tumor marker."Biochem.Biophys.Res.Comm.. 306. 16-25 (2003)
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「研究成果報告書概要(欧文)」より
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[Publications] Kai, M., Nakatsura, T., Egami, H., Senju, S., Nishimura, Y., Ogawa, M.: "Heat shock protein 105 is overexpressed in a variety of human tumors."Oncology reports. 10. 1777-1782 (2003)
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[Publications] Nakatsura, T., Monji, M., Senju, S., Yamada, K., Ogawa, M., Nishimura, Y.: "Identification of cancer antigens by SEREX."Int.Congress Series. 1255. 343-349 (2003)
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[Publications] Uemura, Y., Senju, S., Fujii, S., Iwai, L.K., Maenaka, K., Tabata, H., Kanai, T., Chen, Y-Z., Nishimura, Y.: "Review Specificity, degeneracy, and molecular mimicry in antigen recognition by HLA-class II restricted T cell receptors ; Implications for clinical medicine."Modern Rheumatology. 13. 205-214 (2003)
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「研究成果報告書概要(欧文)」より
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[Publications] Nakatsura, T., Senju, S., Ito, M., Nishimura, Y.^*, Itoh, K.^* (^*equal contribution): "Cellular and Humoral Immune Responses to A Human Pancreatic Cancer Antigen, CLP, Originally Defined by the SEREX Method"Eur.J.Immunol.. 32. 826-836 (2002)
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[Publications] Monji, M., Senju, S., Nakatsura, T., Yamada, K., Sawatsubashi, M., Inokuchi, A., Nishimura Y.: "Head and neck cancer antigens recognized by the humoral immune system"Biochem.Biophys.Res.Commun.. 294. 734-741 (2002)
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