Analysis and application of memory T and memory B cells by applying artificial lymph nodes

• Project/Area Number: 19390142
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Immunology
• Research Institution: Kyoto University (2008); The Institute of Physical and Chemical Research (2007)
• Principal Investigator: WATANABE Takeshi Kyoto University, 大学院・医学研究科, 研究員 (40028684)
• Co-Investigator(Kenkyū-buntansha): KOBAYASHI Yuka 独立行政法人理化学研究所, 特別研究員 (00433590)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥16,900,000 (Direct Cost: ¥13,000,000、Indirect Cost: ¥3,900,000); Fiscal Year 2008: ¥8,060,000 (Direct Cost: ¥6,200,000、Indirect Cost: ¥1,860,000); Fiscal Year 2007: ¥8,840,000 (Direct Cost: ¥6,800,000、Indirect Cost: ¥2,040,000)
• Keywords: 人工免疫組織 / リンパ節 / 記憶T細胞 / 記憶B細胞 / 濾胞性ヘルパーT細胞 / 感染症治療 / 腫瘍免疫 / 再生医学 / 重症感染症の治療 / 人工リンパ節 / メモリーT細胞 / メモリーB細胞 / 抗原特異的二次免疫反応 / 免疫組織再生 / ワクチン

Research Abstract

我々は世界で初めて、自然のリンパ節と類似の構造を持ち、強力な免疫機能を発揮できる移植可能な人工のリンパ節を構築したが、本研究では我々の作製した人工リンパ節において自然のリンパ節では到達し得ないほどの爆発的な二次免疫反応が効率的に誘導されてくることがわかった。我々の人工リンパ節を応用することで非常に高い親和性を持つ治療用モノクローナル抗体の作出が容易に可能となる。我々の作製した人工リンパ節では抗原特異的な記憶ヘルパーT細胞、記憶B細胞が高率に集積してくること、抗原刺激後には濾胞性ヘルパーT(TFH)細胞が高率に人工リンパ節内で分化、増殖してくること、増殖したTFHヘルパーT細胞からのサイトカインIL-21により、抗原刺激を受けたB細胞あるいはCD8陽性キラーT細胞の爆発的な増殖、分化が誘導されることがわかった。しかしながら、抗原特異的なIgGクラスの抗体が大量に産生されてくるにも拘らず、人工リンパ節においては自己抗体の産生は全く見られない。我々の人工リンパ節はヒト免疫系の修復、強化、再生など臨床応用に発展する可能性がある。

Research Products

• [Journal Article] Inhibition of histamine-mediated signaling confers significant protection against severe malaria in mouse model of disease (2008)
  • Author(s): Beghdadi, W., Porcherie, A., Dubayle, D., Peronet, R., Huerre, M., Watanabe, T., Ohtsu, H., Louis,J. Mecheri. S.
  • Journal Title: J. Exp. Med. 205 Pages: 395-408
  • Peer Reviewed
• [Journal Article] Inhibition of histamine-mediated signaling confers significant protection against severe malaria in mouse model of disease. (2008)
  • Author(s): W. Beghdadi, A. Porcherie, D. Dubayle, R. Peronet, M. Huerre, T. Watanabe, H. Ohtsu
  • Journal Title: Journal of Experimental Medicine 205 Pages: 395-408
  • Peer Reviewed
• [Journal Article] Interfering with histamine-mediated signaling results in significant protection against severe malaria in mice. (2008)
  • Author(s): W.Beghdadi, T.Watanabe, 他7名
  • Journal Title: Joumal of Experimental Medicine (in press)
  • Peer Reviewed
• [Journal Article] Artificial lymph nodes induce potent secondary immune responses in naive and immunodeficient mice (2007)
  • Author(s): Okamoto, N., Nishimoto, S., Chihara, R., Shimizu, C. and Watanabe, T.
  • Journal Title: J. Clin. Invest. 117 Pages: 997-1007
  • Peer Reviewed
• [Journal Article] Hart. PH Effect of both UVB irradiation and histamine receptor function on allergic responses to an inhaled antigen (2007)
  • Author(s): McGlade, P Gorman , S Lenzo JC, JW Tan, Watanabe T, JJ Finlay Jones, WR Thomas
  • Journal Title: J I mmunol. 178 Pages: 2794-802
  • Peer Reviewed
• [Journal Article] Antigen presentation to lymphocytes. (review). Encyclopedia of life science (2007)
  • Author(s): Udono H, Wang J-O., Watanabe. T.
  • Journal Title: John Wiley & Son, Ltd.
  • Peer Reviewed
• [Journal Article] Rapid hematopoietic progenitor mobilization by sulfated colominic acid (2007)
  • Author(s): Kubonishi, S..Kikuchi, T Yamaguchi S., Tamamura H., N.Fujii, T.Watanabe, F.Arenzana Seisdedos, Ikeda, K. Matsui T., Tani motoi M., Katayama : Y.
  • Journal Title: BBRC 355 Pages: 970-975
  • NAID: 120001384686
  • Peer Reviewed
• [Journal Article] Artificial lymph nodes induce potent secondary immune responses in naive and immunodeficient mice. (2007)
  • Author(s): N.Okamoto, T.Watanabe, 他3名
  • Journal Title: Journal of Clinical Investigation 117 Pages: 997-1007
  • Peer Reviewed
• [Journal Article] Rapid hematopoietic progenitor mobilization by sulfated colominic acid. (2007)
  • Author(s): S.Kubonishi, T.Watanabe, 他9名
  • Journal Title: Biochem.Bioph.Res.Communication 355 Pages: 970-975
  • NAID: 120001384686
  • Peer Reviewed
• [Journal Article] The H1 histamine receptor regulates allergic I ung responses (2006)
  • Author(s): Bryce P.J., Mathias C., Harrison K., Watanabe T., Geha R.S.,.Oettgen H.
  • Journal Title: J. Clin. Invest. 116 Pages: 1624-1632
  • Peer Reviewed
• [Journal Article] Alterations of slesp wake behavioral characteristics and lack of arousal response to H3 receptor antagonist in histamine H1 receptor knockout mice (2006)
  • Author(s): Huang Zhi-Li, Mochizuki, T. Wei-Min Qu, Zong-Yuan Hong, Watanabe, T. Urade, Y. and Hayaishi O.
  • Journal Title: Proc. Natl. Acad. Sci. USA 103 Pages: 4687-4692
  • Peer Reviewed
• [Journal Article] Clinical significance of RCAS1 as a biomarker of uterine cancer (2006)
  • Author(s): K.Sonoda, S.Miyamoto, T.Hirakawa, H.Yagi, F.Yotsumoto, M . N akashi ma, T.Watanabe, H.Nakano
  • Journal Title: Gynecologic Oncology 103 Pages: 924-931
  • Peer Reviewed
• [Journal Article] Cimetidine induces IL 18 production through H2-agonist activity in monocytes (2006)
  • Author(s): Takahashi H. K., Watanabe T. , Yokoyama A., Iwagaki H., Yoshi no T., Tanaka N. and Nishibori M.
  • Journal Title: Mol. Pharmcology 70 Pages: 450-453
  • Peer Reviewed
• [Journal Article] Role of substance P on hi stami ne H3 antagoni st-i nduced scratching behavior in mice (2006)
  • Author(s): Hossen M.A., Inoue, T. Shinmei, Y..Fuii Y, Watanabe T., Kamei C.
  • Journal Title: J. Pharmacol. Sci. 100 Pages: 297-302
  • Peer Reviewed
• [Journal Article] Development of functional human blood and immune systems in N OD/SCI D/I L2 receptor g chain^<null>mice (2005)
  • Author(s): Ishikawa F., Yasukawa, M. LyonsB., Yoshida S., M iyamoto T., Yoshi moto G., WatanabeT., Akashi K., Shultz L.D., Harada M.
  • Journal Title: Blood 106 Pages: 1565-1573
  • Peer Reviewed
• [Presentation] Generation of transplantable lymph node-like tissues and induction of immune responses (2008)
  • Author(s): 渡邊武
  • Organizer: 第38回に本免疫学会(シンポジウム)
  • Place of Presentation: 京都
  • Year and Date: 2008-12-03
• [Presentation] Generation of transplantable lymph node-like tissues and induction of immune responses (2008)
  • Author(s): 渡邊武
  • Organizer: 第38回に本免疫学会(シンポジウム)
  • Place of Presentation: 国立京都国際会館、京都
  • Year and Date: 2008-12-03
• [Presentation] 免疫組織・臓器の構築一リンパ節の人工的構築 (2007)
  • Author(s): 渡邊武
  • Organizer: 日本動物細胞工学会(シンポジウム)
  • Place of Presentation: 東京
  • Year and Date: 2007-10-24
• [Presentation] Generation of artificial lymph nodes and their immunological function (2007)
  • Author(s): 渡邊武
  • Organizer: 理研-日本免疫学会ジョイントシンポジウム
  • Place of Presentation: 横浜
  • Year and Date: 2007-07-26
• [Presentation] Generation of artificial transplantable lymph node tissues and their immunological function (2007)
  • Author(s): T.Watanabe
  • Organizer: RCAI(RIKEN)-Max-Planc Insitute Joint Symposium
  • Place of Presentation: Max-Planc Insitute for InfectionBiology,Berlin,Germay
  • Year and Date: 2007-04-16
• [Remarks] テレビ、新聞報道 : NHK総合テレビニュース平成19年3月16日(午前6時、午前7時、正午)毎日新聞平成19年3月16日朝刊 日本経済新聞平成19年3月16日朝刊 日経産業新聞平成19年3月16日 日刊工業新聞平成19年3月16日 NIKKEINET平成19年3月16日 NewScientist(USA)平成19年3月16日
• [Patent(Industrial Property Rights)] 人工リンパ節 (2008)
  • Inventor(s): 渡邊武 末松佐知子
  • Acquisition Date: 2008-03-21
• [Patent(Industrial Property Rights)] 人工リンパ節を用いた効率, 的な抗原特異的ハイブリドーマの作成法 (2008)
  • Inventor(s): 渡邊武
  • Industrial Property Rights Holder: 独立行政法人理化学研究所
  • Industrial Property Number: 2006-331114
  • Filing Date: 2008-07-12
  • Overseas
• [Patent(Industrial Property Rights)] 癌治療用人工リンパ節 (2007)
  • Inventor(s): 渡邊 武
  • Industrial Property Rights Holder: 理化学研究所
  • Industrial Property Number: 2007-315574
  • Filing Date: 2007-12-06
• [Patent(Industrial Property Rights)] 人工リンパ節を用いた効率的な抗原特異的ハイブリドーマの作成法 (2005)
  • Inventor(s): 渡邊武
  • Industrial Property Rights Holder: 独立行政法人理化学研究所
  • Industrial Property Number: 2005-357949
  • Filing Date: 2005-12-12
  • Overseas