Basic studies for induction of tolerance by a cell-therapy

• Project/Area Number: 25670548
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: General surgery
• Research Institution: Hokkaido University
• Principal Investigator: YAMASHITA KENICHIRO 北海道大学, 医学(系)研究科(研究院), 特任教授 (00399940)
• Co-Investigator(Kenkyū-buntansha): GOTO Ryoichi 北海道大学, 北海道大学病院, 医員 (10645287) ; AOYAGI Takeshi 北海道大学, 北海道大学病院, 医員 (90374347)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 移植免疫 / 免疫抑制性 / 細胞治療 / 分子標的 / 免疫抑制性細胞

Outline of Final Research Achievements

In this study, we performed basic researches on immunoregulatory cells in order to search for new immunosuppressive strategies. We found that tolerogeneic dendritic cells (tDCs) were successfully generated ex-vivo by suppressing activation of either NF-κB or MAPKs in the presence of donor-peptide antigens, and that administration of these tDCs significantly prolonged allograft survival in mice. The inhibition of NF-κB, MAPKs or AP-1/mTOR/p70S6K activation following infusion of donor-leukocytes exerted a potent immunosuppressive effect. In some of these protocols, regulatory T cells (Tregs) were effectively induced in vivo. Coculture of peripheral blood mononuclear cells and allo-antigens together with either CD80/86- or CD40-costimulation blockers induced antigen-specific Tregs that seemed to have a potential utility for clinical immunosuppression.

Research Products

• [Journal Article] Immunosuppressive effects of DTCM-G, a novel inhibitor of the mTOR downstream signaling pathway. (2013)
  • Author(s): Shibasaki S
  • Journal Title: Transplantation Volume: 95 Issue: 4 Pages: 542-550
  • DOI: 10.1097/tp.0b013e31827b3d90
  • Peer Reviewed
• [Presentation] NK026680とdonor specific transfusion併用による免疫修飾効果 (2014)
  • Author(s): 江本 慎、後藤了一、柴崎 晋、長津明久、小野 仁、青柳武史、深井 原、武冨紹信、嶋村 剛、藤堂 省、山下健一郎
  • Organizer: 第50回日本移植学会総会
  • Place of Presentation: 京王プラザホテル（東京都）
  • Year and Date: 2014-09-10 – 2014-09-12
• [Presentation] Immunomodulation induced by a novel immunosuppressant, NK026680 plus donor specific transfusion permits a long-term cardiac allograft survival in mice (2014)
  • Author(s): Emoto S, Goto R, Shibasaki S, Nagatsu A, Ono H, Igarashi R, Aoyagi T, Fukai M, Shimamura T, Saiga K, Taketomi A, Todo S, Yamashita K
  • Organizer: World Transplant Congress 2014
  • Place of Presentation: Moscone West Convention Center, San Francisco, CA, USA
  • Year and Date: 2014-07-26 – 2014-07-31
• [Presentation] Inducion of Operational Tolerance by a Cell Therapy using Donor Ag-pulsed Tregs in Living Donor Liver Transplantation (2014)
  • Author(s): Yamashita K, Goto R, Zaitsu M, Nagatsu A, Oura T, Watanabe M, Aoyagi T, Suzuki T, Shimamura T, Kamiyama T, Sato N, Sugita J, Hatanaka K, Demetris AJ, Bashuda H, Okumura K, Todo S
  • Organizer: World Transplant Congress 2014
  • Place of Presentation: Moscone West Convention Center, San Francisco, CA, USA
  • Year and Date: 2014-07-26 – 2014-07-31
• [Presentation] Successful Withdrawal of Immunosuppression by a Cell Therapy Using Donor Ag-pulsed Tregs in Living Donor Liver Transplantation (2014)
  • Author(s): Yamashita K, Goto R, Zaitsu M, Nagatsu A, Oura T, Watanabe M, Aoyagi T, Suzuki T, Shimamura T, Kamiyama T, Sato N, Sugita J, Hatanaka K, Bashuda H, Okumura K, Todo S
  • Organizer: 2014 Joint International Congress of ILTS, ELITA & LICAGE
  • Place of Presentation: Queen Elizabeth II Conference Center, London, UK
  • Year and Date: 2014-06-04 – 2014-06-07
• [Presentation] 抗CD80抗体、抗CD86抗体下共培養により誘導される免疫抑制性細胞の同定 (2014)
  • Author(s): 長津明久、山下健一郎、江本 慎、旭 火華、財津雅昭、小倉正臣、小野 仁、常俊雄介、後藤了一、五十嵐瑠美、場集田 寿、奥村 康、武冨紹信、藤堂省
  • Organizer: 第114回日本外科学会定期学術集会
  • Place of Presentation: 京都国際会館（京都市）
  • Year and Date: 2014-04-03 – 2014-04-05
• [Presentation] EX-VIVO GENERATION OF HUMAN REGULATORY T CELLS BY CD80/CD86 COSTIMULATION BLOCKADE (2013)
  • Author(s): Akihisa Nagatsu, Kenichiro Yamashita, Masaaki Zaitsu, Shin Emoto, Yoh Asahi, Hitoshi Ono, Ryoichi Goto, Hisashi Bashuda, Akinobu Taketomi, Ko Okumura, Satoru Todo
  • Organizer: 16th Congress of the European Society for Organ Transplantation
  • Place of Presentation: Austria Centre Vienna (ACV), Vienna, Austria