IL-27による造血幹細胞の運命決定メカニズムの解明

• Project Area: Molecular mechanisms of cell fate determination in the cells that undergo stepwise differentiation to multiple pathways
• Project/Area Number: 25118727
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Tokyo Medical University
• Principal Investigator: 善本 隆之 東京医科大学, 医学部, 教授 (80202406)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: IL-27 / 造血幹細胞 / ミエロイド系前駆細胞

Outline of Annual Research Achievements

(1) IL-27+幹細胞因子（SCF）が作用する細胞の解析：昨年、細胞表面マーカーを組みあわせて種々の骨髄前駆細胞をFACSを用いてソーティングし精製し、骨髄細胞の中でIL-27+SCFが作用する細胞を検討したところ、いわゆるLSK（Lineage陰性c-Kit陽性ScaI陽性）細胞のみが強く反応することを見出した。そこで、さらにもっと詳細に調べたところ、IL-27+SCFは、長期間の骨髄再構築能を有する造血幹細胞（LT-HSC: CD34－CD150+CD41－LSK）とそのミエロイド系細胞に特化した前駆細胞（MyRP: CD34－CD150+CD41+LSK）を長期間に渡り分化増殖を誘導することを明らかにした。

(2) IL-27+幹細胞因子（SCF）が増やした細胞の解析：昨年IL-27+SCFで増えてくる細胞は、ミエロイド系の前駆細胞であることが示唆された。そこで、さらにin vitroの造血細胞への分化誘導の実験系を用いて詳細に検討した。その結果、IL-27+SCFで増えてくる細胞は、M-CSF+Flt3－CD16/32+LSK細胞であり、プライマリーの骨髄細胞由来のLSK細胞に比べて、特に好中球への分化能が亢進しており、反対にFlt3リガンドとトロンボポエチンで分化誘導する形質細胞様樹状細胞(pDC)への分化能は殆ど消失していた。さらに、転写因子として、ミエロイド系分化重要なSpiやGfi1、Cebpa発現が高かった。

Research Progress Status

26年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

26年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Intratumoral CD4+ T lymphodepletion sensitizes poorly immunogenic melanomas to immunotherapy with an OX40 agonist. (2014)
  • Author(s): Fujiwara, S., Nagai, H., Shimoura, N., Oniki, S., Yoshimoto, T., and Nishigori, C.
  • Journal Title: J. Invest. Dermatol. Volume: 134 Issue: 7 Pages: 1884-1892
  • DOI: 10.1038/jid.2014.42
  • Peer Reviewed
• [Journal Article] Contribution of IL-12/IL-35 common subunit p35 to maintaining the testicular immune privilege (2014)
  • Author(s): Terayama H, Yoshimoto T, Hirai S, Naito M, Qu N, Hatayama N, Hayashi S, Mitobe K, Furusawa J, Mizoguchi I, Kezuka T, Goto H, Suyama K, Moriyama H, Sakabe K, Itoh M.
  • Journal Title: PLoS One Volume: 9 Issue: 4 Pages: e96120-e96120
  • DOI: 10.1371/journal.pone.0096120
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Immunosurveillance markers may predict patients who can discontinue imatinib therapy without relapse. (2014)
  • Author(s): Yoshimoto, T., Mizoguchi, I., Katagiri, S., Tauchi, T., Furusawa, J., Chiba, Y., Mizuguchi, J., Ohyashiki, J. H., and Ohyashiki, K.
  • Journal Title: Oncoimmunology Volume: 3
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Down-regulated microRNA-148b in circulating PBMCs in chronic myeloid leukemia patients with undetectable minimal residual disease: A possible molecular classifier to stop imatinib safely. (2014)
  • Author(s): Ohyashiki, J. H., Ohtsuki, K., Mizoguchi, I., Yoshimoto, T., Katagiri, S., Umezu, T., and Ohyashiki, K.
  • Journal Title: Drug Des. Devel. Ther. Volume: 8 Pages: 1151-1159
  • DOI: 10.2147/dddt.s66812
  • Peer Reviewed / Open Access
• [Journal Article] Immunological control of chronic myeloid leukemia leading to treatment-free remission. (2014)
  • Author(s): Mizoguchi, I., Yoshimoto, T., Katagiri, S., Furusawa, J., Chiba, Y., Mizuguchi, J., Tauchi, T., Ohyashiki, J. H., and Ohyashiki, K.
  • Journal Title: J. Hematol. Transfus. Volume: 2(3) Pages: 1024-1024
  • Peer Reviewed
• [Journal Article] IL-27 promotes nitric oxide production induced by LPS through STAT1, NF-kB and MAPKs (2013)
  • Author(s): Shimizu, et al.
  • Journal Title: Immunobiology Volume: 218 Issue: 4 Pages: 628-634
  • DOI: 10.1016/j.imbio.2012.07.028
  • Peer Reviewed
• [Journal Article] Sustained up-regulation of effector natural killer cells in chronic myeloid leukemia after discontinuation of imatinib. (2013)
  • Author(s): Mizoguchi, I., Yoshimoto, T., Katagiri, S., Mizuguchi, J., Tauchi, T., Kimura, Y., Inokuchi, K., Ohyashiki, J. H., and Ohyashiki, K.
  • Journal Title: Cancer Sci. Volume: 104 Issue: 9 Pages: 1146-1153
  • DOI: 10.1111/cas.12216
  • Peer Reviewed
• [Journal Article] The ARNT-STAT axis regulates the differentiation of intestinal intraepithelial TCRαβ+CD8αα+cells. (2013)
  • Author(s): Nakajima K, Maekawa K, Kataoka K, Ishifune C, Nishida J, Arimochi H, Yoshimoto T, Tomita S, Nagahiro S, Yasutomo K.
  • Journal Title: Nature Communications Volume: 4 Issue: 1 Pages: 1-11
  • DOI: 10.1038/ncomms3112
  • Peer Reviewed
• [Journal Article] Pivotal Roles of T-Helper 17-Related Cytokines, IL-17, IL-22, and IL-23, in Inflammatory Diseases. (2013)
  • Author(s): Qu N, Xu M, Mizoguchi I, Furusawa J, Kaneko K, Watanabe K, Mizuguchi J, Itoh M,Kawakami Y, Yoshimoto T.
  • Journal Title: Clin Dev Immunol. Volume: 2013:968549 Pages: 1-13
  • DOI: 10.1155/2013/968549
  • Peer Reviewed
• [Journal Article] IL-27 enhances the expression of TRAIL and TLR3 in human melanomas and inhibits their tumor growth in cooperating with a TLR3 agonist poly(I:C) partly in TRAIL-dependent manner (2013)
  • Author(s): Chiba Y, Mizoguchi K, Mitobe I, Higuchi K, Nagai H, Nishigori C, Mizuguchi J, Yoshimoto T
  • Journal Title: PLoS One Volume: 8(10) Issue: 10 Pages: e76159-e76159
  • DOI: 10.1371/journal.pone.0076159
  • Peer Reviewed
• [Presentation] IL-27 exerts potent antitumor activity by promoting the differentiation of hematopoietic stem cells to M1-like antitumor macrophages and their mobilization. (2014)
  • Author(s): Chiba, Y., Furusawa, J., Mizoguchi, I., Xu, M., Mizuguchi, J., and Yoshimoto, T.
  • Organizer: 第43回日本免疫学会総会・学術集会
  • Place of Presentation: 京都
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] IL-27 promotes the differentiation of hematopoietic stem cells into multipotent myeloid progenitor cells. (2014)
  • Author(s): Furusawa, J., Chiba, Y., Mizoguchi, I., Xu, M., Mizuguchi, J., and Yoshimoto, T.
  • Organizer: 第43回日本免疫学会総会・学術集会
  • Place of Presentation: 京都
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] PepTivator® OVA-pulsed DCs can induce both OVA specific CD8+ and CD4+ T cells in mouse model. (2014)
  • Author(s): Miki, K., Nagaoka, K., Yoshimoto, T., Kamigaki, T. and Maekawa, R.
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Regulation of antitumor immune responses through differentiation and mobilization of hematopoietic stem cells by IL-27. (2014)
  • Author(s): Chiba, Y., Mizoguchi, I., Hisada, M., Tsuchida, A., Mizuguchi, J., and Yoshimoto, T.
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] IL-27 promotes the differentiation of hematopoietic stem cells into DC progenitor cells. (2014)
  • Author(s): Furusawa, J., Chiba, Y., Mitobe, K., Mizoguchi, I., Mizuguchi, J., and Yoshimoto, T.
  • Organizer: 13th International Symposium on Dendritic Cells, DC2014
  • Place of Presentation: Tours, France
  • Year and Date: 2014-09-14 – 2014-09-18
• [Presentation] Contribution of IL-35 to maintaining the testicular immune privilege. (2014)
  • Author(s): Terayama, H., Naito, M., Yoshimoto, T., Hirai, S., Qu, N., Kuramasu, M., Hatayama, N., Kanazawa, T., Suyama, K., Sakabe, K., and Itoh, M.
  • Organizer: 第33回日本アンドロロジー学会学術大会
  • Place of Presentation: 軽井沢
  • Year and Date: 2014-06-12 – 2014-06-13
• [Presentation] Induction of antigen specific T cells using PepTivator®-pulsed DCs. (2014)
  • Author(s): Takahara, M., Goto, S., Miki, K., Saiwaki, S., Nagaoka, K., Matsushita, H., Kondo, T. Bohnenkamp, H., Yoshimoto, T., Maekawa, R., and Kamigaki, T.
  • Organizer: International Society For Cellular Therapy 20th Annual Meeting 2014
  • Place of Presentation: Paris, France
  • Year and Date: 2014-04-23 – 2014-04-26
• [Presentation] Induction of both OVA specific CD4+ and CD8+ T cells by using PepTivator® OVA-pulsed DCs in mouse model. (2014)
  • Author(s): Miki, K., Nagaoka, K., Bohnenkamp, H., Yoshimoto, T., Kamigaki, T. and Maekawa, R.
  • Organizer: American Association for Cancer Research 105th Annual Meeting 2014
  • Place of Presentation: San Diego, California, USA
  • Year and Date: 2014-04-05 – 2014-04-09
• [Presentation] The percentage of effector populations of NK cells correlated highly with sustained CMR with or without imatinib in chronic myeloid leukemia patients. (2013)
  • Author(s): Katagiri, S., Mizoguchi, I., Yoshimoto, T., Mizuguchi, J., Ohyashiki, J.H., Tauchi, T., Inokuchi, K., and Ohyashiki, K.
  • Organizer: 18th Congress of the European Hematology Association
  • Place of Presentation: Stockholm, Sweden
• [Presentation] EBI3 functions as an intracellular molecule to regulate the development of colitis in naive CD4+CD25- T cells. (2013)
  • Author(s): Mizoguchi, I. Mitobe, K., Tsunoda, R., Higuchi, K., Mizuguchi, J., and Yoshimoto, T.
  • Organizer: 15th International Congress of Immunology
  • Place of Presentation: Milan, Italy
• [Presentation] New approach for DC-mediated cancer vaccine using IL-27-expanded myeloid progenitor cells. (2013)
  • Author(s): Yoshimoto, T., Mizoguchi, I. Hisada, M., and Mizuguchi, J.
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] Long-term up-regulation of effector NK cells in CML after stopping imatinib. (2013)
  • Author(s): Katagiri, S., Mizoguchi, I., Yoshimoto, T., Ohyashiki, J.H., Tauchi, T., Inokuchi, K., and Ohyashiki, K.
  • Organizer: 第75回日本血液学会学術集会
  • Place of Presentation: 横浜
• [Presentation] IL-27 promotes the differentiation of bone marrow cells into DC progenitor cells. (2013)
  • Author(s): Furusawa, J., Mizoguchi, I., Mizuguchi, J., and Yoshimoto, T.
  • Organizer: 第42回日本免疫学会総会
  • Place of Presentation: 幕張
• [Book] Cytokine Frontiers: Regulation of Immune Responses in Health and Disease. (2013)
  • Author(s): Yoshimoto, T. and Yoshimoto, T (Editors)
  • Total Pages: 396
  • Publisher: Springer