免疫老化、自己免疫疾患発症における胸腺髄質上皮細胞の変容とその意義

• Project Area: Analysis and synthesis of multi-dimensional immune organ network
• Project/Area Number: 25111505
• 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: Kyoto University
• Principal Investigator: 濱崎 洋子 京都大学, 医学(系)研究科(研究院), 准教授 (10362477)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥11,570,000 (Direct Cost: ¥8,900,000、Indirect Cost: ¥2,670,000); Fiscal Year 2014: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2013: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
• Keywords: 胸腺 / 胸腺上皮細胞 / 幹細胞 / 胸腺退縮 / 自己免疫疾患 / 中枢性自己寛容

Outline of Annual Research Achievements

昨年度までに、自己寛容を保証する胸腺髄質上皮幹細胞の存在を証明し、かつその活性が生後直後に急速に低下することが明らかとなり、それらの点について論文としてまとめることができた。本年度は、中枢性自己寛容を担う髄質上皮細胞の何らかの異常と、自己免疫疾患発症との関連を様々な自己免疫モデルマウスを用いて検討した。その結果、全身性自己免疫疾患であるＳＬＥのマウスモデルが、髄質上皮細胞の発生異常を呈することが明らかとなった。　そこで、胸腺髄質上皮幹細胞の同定とその活性の評価に大きな役割を果たした培養系を用いて、本マウスの胸腺上皮コロニー形成能について検討したところ、Ｂ６マウスと比較して新生児の時点て明らかにコロニー形成能が低いことが分かった。以上の結果は、ＳＬＥモデルマウスで認められるＴ細胞の機能異常が、胸腺髄質上皮細胞の発生異常に起因する可能性があること、またこの発生異常が幹細胞レベルで起こっている可能性を示唆するものである。

Research Progress Status

27年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

27年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Medullary thymic epithelial stem cells: role in thymic epithelial cell maintenance and thymic involution (2016)
  • Author(s): Hamazaki Y, Sekai M, Minato N.
  • Journal Title: Immunol Rev. Volume: 印刷中
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Relb acts downstream of medullary thymic epithelial stem cells and is essential for the emergence of RANK+ medullary epithelial progenitors. (2016)
  • Author(s): Baik S, Sekai M, Hamazaki Y, Jenkinson WE, Anderson G.
  • Journal Title: Eur J Immunol. Volume: - Issue: 4 Pages: 857-62
  • DOI: 10.1002/eji.201546253
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Adult thymic epithelial cell (TEC) progenitors and TEC stem cells – Models and mechanisms for the development and maintenance of thymic epithelial cells (2015)
  • Author(s): Hamazaki Y.
  • Journal Title: Eur J Immunol. Volume: 45 Issue: 11 Pages: 2985-93
  • DOI: 10.1002/eji.201545844
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Adult thymic medullary epithelium is maintained and regenerated by lineage-restricted cells rather than bipotent progenitors (2015)
  • Author(s): Ohigashi I, Zuklys S, Sakata M, Mayer CE, Hamazaki Y, Minato N, Hollander GA, Takahama Y.
  • Journal Title: Cell Rep. Volume: 13 Issue: 7 Pages: 1432-43
  • DOI: 10.1016/j.celrep.2015.10.012
  • NAID: 120006727050
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A CD153+CD4+ T follicular cell population with cell-senescence features plays a crucial role in lupus pathogenesis via osteopontin production. (2015)
  • Author(s): 1.Tahir S, Fukushima Y, Sakamoto K, Sato K, Fujita H, Inoue J, Uede T, Hamazaki Y, Hattori M, Minato N.
  • Journal Title: The Journal of Immunology Volume: 194 Issue: 12 Pages: 5725-5735
  • DOI: 10.4049/jimmunol.1500319
  • Peer Reviewed / Open Access
• [Journal Article] Crucial role of the Rap G protein signal in Notch activation and leukemogenicity of T-cell acute lymphoblastic leukemia. (2015)
  • Author(s): Doi K, Imai T, Kressler C, Yagita H, Agata Y, Vooijs M, Hamazaki Y, Inoue J, Minato N.
  • Journal Title: Sci Rep. Volume: 5 Issue: 1 Pages: 7978-7985
  • DOI: 10.1038/srep07978
  • NAID: 120005555511
  • Peer Reviewed / Open Access
• [Journal Article] Medullary thymic epithelial stem cells maintain a functional thymus to ensure lifelong central T cell tolerance. (2014)
  • Author(s): Sekai M, Hamazaki Y, Minato N.
  • Journal Title: Immunity. Volume: 41 Issue: 5 Pages: 753-761
  • DOI: 10.1016/j.immuni.2014.10.011
  • Peer Reviewed / Open Access
• [Journal Article] In vivo imaging reveals PKA regulation of ERK activity during neutrophil recruitment to inflamed intestines. (2014)
  • Author(s): Mizuno, R., Kamioka, Y., Kabashima, K., Imajo, M., Sumiyama, K., Nakasho, E., Ito, T., Hamazaki, Y., Okuchi, Y., Sakai, Y., Kiyokawa, E., and Matsuda, M.
  • Journal Title: J Exp Med Volume: 211 Issue: 6 Pages: 1123-36
  • DOI: 10.1084/jem.20132112
  • NAID: 120005439165
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Enteroendocrine cells are specifically marked by cell surface expression of claudin-4 in mouse small intestine (2014)
  • Author(s): Nagatake T, Fujita H, Minato N, Hamazaki Y.
  • Journal Title: PLoS One Volume: 9 Issue: 3 Pages: e90638-e90638
  • DOI: 10.1371/journal.pone.0090638
  • Peer Reviewed / Open Access
• [Presentation] Medullary thymic epithelial stem cells ensuring lifelong T-cell tolerance (2016)
  • Author(s): Yoko Hamazaki
  • Organizer: The Fifth Bizan Immunology Symposium at University of Tokushima (BISUT5) “Immune System Development, Deviation, and Regulation”
  • Place of Presentation: Nichia Medical Hall, Kuramoto Campus, University of Tokushima （Tokushima)
  • Year and Date: 2016-03-03
  • Int'l Joint Research / Invited
• [Presentation] Medullary Thymic Epithelial Stem Cells Ensuring Lifelong Central T cell Tolerance (2016)
  • Author(s): Yoko Hamazaki
  • Organizer: Environment controlling normal and diseased hematopoietic and immune systems (Sponsored by MEXT Research Project on Analysis and Synthesis of Multidimensional Immune Organ Network and RIKEN IMS)
  • Place of Presentation: RIKEN Yokohama Research Institute 6F seminar room (Yokohama)
  • Year and Date: 2016-03-02
  • Int'l Joint Research / Invited
• [Presentation] 胸腺における中枢性自己寛容の成立と胸腺退縮に伴うＴ細胞の加齢変化 (2015)
  • Author(s): 濱崎洋子
  • Organizer: CREATE 2015（Cardio-Renal Interaction and Translational Research Enhancement）
  • Place of Presentation: ロイヤルパークホテル（東京)
  • Year and Date: 2015-09-25
  • Invited
• [Presentation] 免疫系・内分泌系細胞に発現するクローディンとその意義 (2015)
  • Author(s): 濱崎 洋子
  • Organizer: 日本薬学会 第135年会 シンポジウム「上皮を標的とした創薬研究の新展開」
  • Place of Presentation: 神戸学院大学（神戸）
  • Year and Date: 2015-03-27
  • Invited
• [Presentation] 免疫老化 (2015)
  • Author(s): 濱崎 洋子
  • Organizer: 日本抗加齢医学会 専門医・指導士認定委員会主催講習会
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 2015-03-22
  • Invited
• [Presentation] 中枢性免疫寛容を担う胸腺髄質上皮細胞の発生とその維持 (2015)
  • Author(s): 濱崎 洋子
  • Organizer: 第３４回 日本胸腺研究会 ミニシンポジウム「胸腺の形成と維持 最近の話題
  • Place of Presentation: 相模原市立市民・大学交流センター ユニコムプラザさがみはら
  • Year and Date: 2015-02-07
  • Invited
• [Presentation] Identification of medullary thymic epithelial stem cells ensuring lifelong central T-cell tolerance (2014)
  • Author(s): Yoko Hamazaki
  • Organizer: 第４３回日本免疫学会学術集会 国際シンポジウム Thymic microenvironments for T cell development and repertoire formation
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2014-12-10
  • Invited
• [Presentation] Thymic Medullary Epithelial Stem Cells Ensuring Lifelong Central T-cell Tolerance (2014)
  • Author(s): Yoko Hamazaki
  • Organizer: The 24th Hot Spring Harbor International Symposium 「Recent Advance in Immunology and Inflammation」
  • Place of Presentation: 九州大学 生体防御医学研究所
  • Year and Date: 2014-11-07
  • Invited
• [Presentation] 中枢性免疫寛容を担う胸腺上皮細胞の発生とその維持 (2014)
  • Author(s): 濱崎 洋子
  • Organizer: 第一回皮膚免疫カンファレンス 特別講演
  • Place of Presentation: 六本木ヒルズ（東京）
  • Year and Date: 2014-07-19
  • Invited
• [Presentation] 中枢性免疫寛容を担う胸腺上皮細胞の発生とその維持 (2014)
  • Author(s): 濱崎 洋子
  • Organizer: 第５１回日本消化器免疫学会総会 教育講演
  • Place of Presentation: 京都大学芝蘭会館
  • Year and Date: 2014-07-10
  • Invited