A novel strategy for treatment of diabetes by immuneregulation(Fostering Joint International Research)

• Project/Area Number: 15KK0355
• Research Category: Fund for the Promotion of Joint International Research (Fostering Joint International Research)
• Allocation Type: Multi-year Fund
• Research Field: General surgery
• Research Institution: Tokyo Women's Medical University
• Principal Investigator: Hirai Toshihito 東京女子医科大学, 医学部, 助教 (70722693)
• Project Period (FY): 2016 – 2019
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥9,750,000 (Direct Cost: ¥7,500,000、Indirect Cost: ¥2,250,000)
• Keywords: 移植免疫寛容 / 制御性T細胞 / iNKT細胞 / 移植片対宿主病 / IL-2 / 細胞工学 / 免疫寛容 / 遺伝子導入 / 細胞工学療法 / 調整性T細胞 / IL2 / OX40 / 臓器移植拒絶 / 調節性T細胞 / 自然免疫 / 糖尿病 / ナチュラルキラーT細部 / 臓器拒絶

Outline of Final Research Achievements

Regulatory T cells (Tregs) and invariant natural killer T cells (iNKTs) play an important role in immune tolerance. In this study, we demonstrated that graft-versus-host disease (GvHD) and islet rejection can be suppressed by activating recipient iNKTs at the time of transplantation. We also developed a mutant IL-2/IL-2 receptor pair that specifically binds each other. When Tregs were transferred into the recipient mice after transducing this mutant IL-2 receptor, the injection of mutant IL-2 selectively activated transferred Tregs and successfully mitigated organ rejection.

Academic Significance and Societal Importance of the Research Achievements

本研究で開発された新たな手法により、Treg細胞療法の臨床応用がより安全に実現可能となる。Treg細胞療法は移植医療のみならず、免疫破綻が原因の様々な自己免疫疾患やアレルギー疾患治療への適応が可能である。本研究が、生涯に渡り免疫抑制剤の内服が必要な患者の副作用軽減とQOL改善につながることが期待される。

Research Products

• [Int'l Joint Research] Stanford University(米国) (2016)
  • Year and Date: 2016-09-01
• [Presentation] Engineered IL-2 Cytokine-Cytokine Receptor Complex Enables Selective Expansion of Regulatory T Cells and Facilitates Establishment of Organ Transplantation Tolerance (2020)
  • Author(s): T.Hirai, F.Simonetta, L.L.Su, et al
  • Organizer: アメリカ骨髄移植移植、細胞治療学会2020
  • Int'l Joint Research
• [Presentation] Orthogonal IL-2 Cytokine-receptor Pair Capable Of Selective Expansion Of Regulatory T Cells Facilitates Alloengraftment (2020)
  • Author(s): T.Hirai, F.Simonetta, L.L.Su, et al
  • Organizer: アメリカ移植学会2020
  • Int'l Joint Research
• [Presentation] Imaging OX40+Alloreactive T Cells Provides Early Warning Of Organ Transplant Rejection (2020)
  • Author(s): T.Hirai, A.Mayer, T.W.Nobashi. et al.
  • Organizer: アメリカ移植学会2020
  • Int'l Joint Research
• [Presentation] iNKT cell stimulation with liposomal alpha/Gal/Cer amplifies proliferation of adoptively transferred regulatory T cells in vivo and reduces GVHD (2018)
  • Author(s): Toshihito Hirai, Federico Simonetta, Kristina Maas-Bauer, Melissa Mavers, Jeanette Baker, and Robert S Negrin
  • Organizer: 61st ASH meeting
  • Int'l Joint Research
• [Presentation] Treatment of donors with liposomal alpha-galactosylceramide results in the in vivo expansion of invariant natural killer T cells and reduced incidence of acute graft versus host disease (2017)
  • Author(s): Toshihito Hirai, Federico Simonetta, Kristina Mass-Bauer, Jeanette Baker, Mustafa Tukoz, Maite Alvarez, Melissa Mavers, Robert S Negrin
  • Organizer: The American Society of Hematology (ASH) 2017
  • Int'l Joint Research