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Development of the technology for the synthesis of functional human lymphoid tissues

Planned Research

Project AreaAnalysis and synthesis of multi-dimensional immune organ network
Project/Area Number 24111009
Research Category

Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionThe Tazuke Kofukai (2014-2016)
Kyoto University (2012-2013)

Principal Investigator

WATANABE Takeshi  公益財団法人田附興風会, 医学研究所, 特任研究指導者 (40028684)

Co-Investigator(Kenkyū-buntansha) 石川 文彦  国立研究開発法人理化学研究所, 統合生命医科学研究センター, グループディレクター (30403918)
Project Period (FY) 2012-06-28 – 2017-03-31
Project Status Completed (Fiscal Year 2016)
Budget Amount *help
¥118,950,000 (Direct Cost: ¥91,500,000、Indirect Cost: ¥27,450,000)
Fiscal Year 2016: ¥25,220,000 (Direct Cost: ¥19,400,000、Indirect Cost: ¥5,820,000)
Fiscal Year 2015: ¥22,750,000 (Direct Cost: ¥17,500,000、Indirect Cost: ¥5,250,000)
Fiscal Year 2014: ¥25,350,000 (Direct Cost: ¥19,500,000、Indirect Cost: ¥5,850,000)
Fiscal Year 2013: ¥20,540,000 (Direct Cost: ¥15,800,000、Indirect Cost: ¥4,740,000)
Fiscal Year 2012: ¥25,090,000 (Direct Cost: ¥19,300,000、Indirect Cost: ¥5,790,000)
Keywordsヒト型人工リンパ節 / ストローマ細胞 / スフェロイド形成 / 抗原特異的免疫反応 / がん免疫療法 / 免疫組織再生 / 徐放性ゲル / 特異的免疫反応 / ガン免疫療法 / T細胞 / B細胞 / 樹状細胞 / 免疫反応 / 感染防御 / がん治療 / ヒト型人工リンパ組織 / 免疫反応誘導 / がん免疫 / 免疫不全症 / 人工リンパ節 / 免疫不全 / 免疫学 / 再生医学 / リンパ組織 / 感染症 / がん / 老化 / インデューサー細胞
Outline of Final Research Achievements

We have succeeded to establish the technology to construct human type artificial lymphoid tissues. We first established human lymphoid tissue stromal cells from human mesenchymal stem cells. The stromal cells were then cultured with recombinant human collagen peptides, which formed spheroids of the stromal cells. The spheroids and human peripheral blood lymphocytes were mixed and transplanted into renal subcapsular space of immunodeficient NSG mice. After 2-3 weeks, human lymph node-like tissues were formed at high efficiency. The tissues are composed of B cell follicles with FDC network, T cell areas containing FRC networks and dendritic cells. They contain fine networks of blood vessels with HEV, and lymph vessels. Antigen-specific antibody production and T cell responses were efficiently induced upon antigen stimulation.The structure of the tissues is stably maintained in NSG mice and easy to remove and transplant.

Report

(6 results)
  • 2016 Annual Research Report   Final Research Report ( PDF )
  • 2015 Annual Research Report
  • 2014 Annual Research Report
  • 2013 Annual Research Report
  • 2012 Annual Research Report

Research Products

(30 results)

All 2017 2016 2015 2014 2013 2012

All Journal Article (23 results) (of which Int'l Joint Research: 5 results,  Peer Reviewed: 23 results,  Open Access: 15 results,  Acknowledgement Compliant: 9 results) Presentation (5 results) (of which Int'l Joint Research: 1 results,  Invited: 1 results) Book (2 results)

  • [Journal Article] Stromal Cell Subsets Directing Neonatal Spleen Regeneration.2017

    • Author(s)
      Tan JK, Watanabe T.
    • Journal Title

      Sci Rep

      Volume: 7 Issue: 1 Pages: 40401-40401

    • DOI

      10.1038/srep40401

    • NAID

      120005997788

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Thrombomodulin attenuates inflammatory damage due to liver ischemia and reperfusion injury in mice in Toll-like Receptor 4-dependent manner2017

    • Author(s)
      K. Kadono, Y. Uchida, H. Hirao, T. Miyauchi, T. Watanabe, T. Iida, S. Ueda, A. Kanazawa, A. Mori, H. Okajima, H. Terajima, S. Uemoto
    • Journal Title

      American J. of Transplantation

      Volume: 17 Issue: 1 Pages: 69-80

    • DOI

      10.1111/ajt.13991

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Gel-trapped lymphorganogenic chemokines trigger artificial tertiary lymphoid organs and mount adaptive immune responses in vivo.2016

    • Author(s)
      Kobayashi Y, Watanabe T.
    • Journal Title

      Front Immunol

      Volume: 7 Pages: 316-316

    • DOI

      10.3389/fimmu.2016.00316

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] A rare subset of skin-tropic regulatory T cells expressing Il10/Gzmb inhibits the cutaneous immune response.2016

    • Author(s)
      Ikebuchi R, Teraguchi S, Vandenbon A, Honda T, Shand FH, Nakanishi Y, Watanabe T, Tomura M.
    • Journal Title

      Sci Rep. 6: 35002, doi:

      Volume: 6 Issue: 1 Pages: 35002-35002

    • DOI

      10.1038/srep35002

    • NAID

      120006223629

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Role of histamine H1-receptor on behavioral states and wake maintenance during deficiency of a brain activating system: A study using a knockout mouse model.2016

    • Author(s)
      Parmentier R, Zhao Y, Perier M, Akaoka H, Lintunen M, Hou Y, Panula P, Watanabe T, Franco P, Lin JS
    • Journal Title

      Neuropharmacology

      Volume: なし Pages: 20-34

    • DOI

      10.1016/j.neuropharm.2015.12.014

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Induction of WT1-specific human CD8+ T cells from human HSCs in HLA class I Tg NOD/SCID/IL2rgKO mice.2016

    • Author(s)
      Najima Y, Tomizawa-Murasawa M, Saito Y, Watanabe T, Ono R, Ochi T, Suzuki N, Fujiwara H, Ohara O, Shultz LD, Yasukawa M, Ishikawa F.
    • Journal Title

      Blood

      Volume: 127(6) Issue: 6 Pages: 722-734

    • DOI

      10.1182/blood-2014-10-604777

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] TGF-β induces the differentiation of human CXCL13-producing CD4+ T cells.2016

    • Author(s)
      Kobayashi S, Watanabe T, Suzuki R, Furu M, Ito H, Ito J, Matsuda S, Yoshitomi H
    • Journal Title

      Eur J Immunol

      Volume: 46 Issue: 2 Pages: 360-371

    • DOI

      10.1002/eji.201546043

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Aquaporin-3 mediated hydrogen peroxide transport required for NF-kB signaling in epidermal keratinocytes and development of psoriasis.2015

    • Author(s)
      Hara-Chikuma M, Satooka H, Miyachi Y, Watanabe T, Verkman AS
    • Journal Title

      Nat Commun.

      Volume: 6 Issue: 1 Pages: 7454-7454

    • DOI

      10.1038/ncomms8454

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] The protective function of galectin-9 in liver ischemia and reperfusion injury in mice.2015

    • Author(s)
      Hirofumi Hirao, Yoichiro Uchida, Kentaro Kadono, Hirokazu Tanaka, Toshiro Niki, Akira Yamauchi, Koichiro Hata, Takeshi Watanabe, Hiroaki Terajima, Shinji Uemoto
    • Journal Title

      Liver Transplantation

      Volume: 21 Issue: 7 Pages: 969-981

    • DOI

      10.1002/lt.24159

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Tracking and quantification of dendritic cell migration and antigen trafficking between the skin and lymph nodes.2014

    • Author(s)
      Tomura M, Hata A, Matsuoka S, Shand FH, Nakanishi Y, Ikebuchi R, Ueha S, Tsutsui H, Inaba K, Matsushima K, Miyawaki A, Kabashima K, Watanabe T, Kanagawa O.
    • Journal Title

      Sci Rep.

      Volume: 4 Issue: 1 Pages: 6030-6030

    • DOI

      10.1038/srep06030

    • NAID

      120005749847

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Murine spleen tissue regeneration from neonatal spleen capsule requires lymphotoxin priming of stromal cells2014

    • Author(s)
      Tan J, Watanabe T.
    • Journal Title

      Journal of Immunology

      Volume: 193 Pages: 1194-1194

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Meis1 is required for the maintenance of postnatal thymic epithelial cells.2014

    • Author(s)
      Hirayama T, Asano Y, Iida H, Watanabe T, Nakamura T, Goitsuka R.
    • Journal Title

      PLOS One

      Volume: 9 Issue: 3 Pages: e89885-e89885

    • DOI

      10.1371/journal.pone.0089885

    • Related Report
      2014 Annual Research Report 2013 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Modulation of the human T cell response by a novel non-mitogenic anti-CD3 antibody.2014

    • Author(s)
      Shiheido H, Chen C, Hikida M, Watanabe T, Shimizu J.
    • Journal Title

      PLoS One.

      Volume: 9 Issue: 4 Pages: e94324-e94324

    • DOI

      10.1371/journal.pone.0094324

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Human T cells expressing BEND3 on their surface represent a novel subpopulation that preferentially produces IL-6 and IL-8.2014

    • Author(s)
      Shiheido H, Kitagori K, Sasaki C, Kobayashi S, Aoyama T, Urata K, Oku T, Hirayama Y, Yoshitomi H, Hikida M, Yoshifuji H, Mimori T, Watanabe T, Shimizu J.
    • Journal Title

      Immunity, Inflammation and Disease.

      Volume: 2 Issue: 1 Pages: 35-43

    • DOI

      10.1002/iid3.17

    • Related Report
      2014 Annual Research Report 2013 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A novel CD3-specific antibody induces immunosuppression via impaired phosphorylation of LAT and PLCγ1 following T-cell stimulation2014

    • Author(s)
      Shiheido H, Aoyama T, Takahashi H, Hanaoka K, Abe T, Nishida E, Chen C, Koga O, Hikida M, Shibagaki Y, Morita A, Nikawa T, Hattori S, Watanabe T, Shimizu J.
    • Journal Title

      European Journal of Immunology

      Volume: 44 Pages: 1770-1770

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Modulation of the human T cell response by a novel non-mitogenic anti-CD3 antibody2014

    • Author(s)
      Shiheido H, Chen C, Hikida M, Watanabe T, Shimizu J.
    • Journal Title

      PLoS One

      Volume: 未定

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A novel CD3-specific antibody induces immunosuppression via impaired phosphorylation of LAT and PLCγ1 following T-cell stimulation2014

    • Author(s)
      Shiheido H, Aoyama T,Takahashi H, Hanaoka K, Abe T, Nishida E, Chen C, Koga O, Hikida M, Shibagaki Y, Morita A, Nikawa T, Hattori S, Watanabe T,Shimizu J.
    • Journal Title

      European Journal of Immunology

      Volume: 未定

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A distinct human CD4+ T cell subset that secretes CXCL13 in rheumatoid synovium2013

    • Author(s)
      Kobayashi S, Miura K, Shibuya H, Morita M, Ishikawa M, Furu M, Ito H, Matsuda S, Watanabe T, Yoshitomi H.
    • Journal Title

      Arthritis Rheum

      Volume: 65 Issue: 12 Pages: 3063-3072

    • DOI

      10.1002/art.38173

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Basophils are required for the induction of Th2 immunity to haptens and peptide antigens.2013

    • Author(s)
      Otsuka A, Nakajima S, Kubo M, Egawa G, Honda T, Kitoh A, Nomura T, Hanakawa S, Sagita Moniaga C, Kim B, Matsuoka S, Watanabe T, Miyachi Y , Kabashima K.
    • Journal Title

      Nature Communications

      Volume: 4 Issue: 1 Pages: 1739-1739

    • DOI

      10.1038/ncomms2740

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Histamine receptor 2 modifies dendritic cell responses to microbial ligands2013

    • Author(s)
      Frei F, Ferstl R, Konieczna P, Ziegler M, Simon T, Rugeles TM, Mailand S, Watanabe T, Lauener R, Akdis C, O’Mahony L.
    • Journal Title

      J Allergy Clin Immunol

      Volume: 132 Issue: 1 Pages: 194-204

    • DOI

      10.1016/j.jaci.2013.01.013

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Moesin Controls Clathrin-Mediated S1PR1 Internalization in T Cells.2013

    • Author(s)
      Nomachi A, Yoshinaga M, Liu J, Kanchanawong P, Tohyama K, Thumkeo D, Watanabe T, Narumiya S, Hirata T.
    • Journal Title

      PLoS One

      Volume: 8 Issue: 12 Pages: e82590-e82590

    • DOI

      10.1371/journal.pone.0082590

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Generation and characterization of severe combined immune deficientrats.2012

    • Author(s)
      Mashimo T, Takizawa A, Kobayashi J, Kunihiro Y, Yoshimi K, Ishida S, Tanabe K, Yanagi A, Tachibana A, Hirose J, Yomoda J, Morimoto S, Kuramoto T, Voigt B, Watanabe T, Hiai H, Tateno C, Komatsu K, Serikawa T.
    • Journal Title

      Cell Reports

      Volume: 2(3) Issue: 3 Pages: 685-694

    • DOI

      10.1016/j.celrep.2012.08.009

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Moesin-deficient mice reveal a non-redundant role for moesin in lymphocyte homeostasis.2012

    • Author(s)
      Hirata T., et al
    • Journal Title

      Int Immunol.

      Volume: 24 Issue: 11 Pages: 705-717

    • DOI

      10.1093/intimm/dxs077

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Presentation] The generation of human-type artificial lymphoid tissues (aLTs)2016

    • Author(s)
      小林由佳、渡邊 武
    • Organizer
      第45回日本免疫学会学術集会
    • Place of Presentation
      沖縄県宜野湾市 沖縄コンベンションセンター
    • Year and Date
      2016-12-05
    • Related Report
      2016 Annual Research Report
  • [Presentation] A stromal organiser cell that directs neonatal spleen regeneration2015

    • Author(s)
      Tan J, Watanabe T,
    • Organizer
      ISEH (International Society Experimental Hematology) 44th Annual Meeting
    • Place of Presentation
      京都国際会館会議場
    • Year and Date
      2015-09-17
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Identification of organizer responsible for spleen re-generation from neonatal spleen2014

    • Author(s)
      渡邊 武
    • Organizer
      4th Synthetic Immunology
    • Place of Presentation
      Kyoto, Jsapan
    • Related Report
      2013 Annual Research Report
  • [Presentation] 免疫組織(臓器)の人工的再構築の試みとその可能性について2013

    • Author(s)
      渡邊 武
    • Organizer
      北海道大学創薬ネットワークセミナー
    • Place of Presentation
      札幌市
    • Year and Date
      2013-01-23
    • Related Report
      2012 Annual Research Report
    • Invited
  • [Presentation] Trial of the generation of artificial lymph nodes by a cell-free method2012

    • Author(s)
      小林由佳、他1名
    • Organizer
      第41回日本免疫学会学術集会
    • Place of Presentation
      神戸市
    • Year and Date
      2012-12-05
    • Related Report
      2012 Annual Research Report
  • [Book] Synthetic Immunology2016

    • Author(s)
      Y. Kobayashi, K. Kato, M. Nakamura, T. Watanabe
    • Total Pages
      20
    • Publisher
      Springer Nature
    • Related Report
      2016 Annual Research Report
  • [Book] Synthetic Immunology2016

    • Author(s)
      M. Nakamura, K.Arai, T.Mimura, J.Tagawa, H.Yoshida, K.Kato, T.Nakaji-Hirabayashi, Y.Kobayashi, T.Watanabe
    • Total Pages
      20
    • Publisher
      Springer Nature
    • Related Report
      2016 Annual Research Report

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Published: 2012-11-27   Modified: 2019-07-29  

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