Elucidation of role for HSP90 in allograft rejection after solid organ transplantation and development of novel treatment strategy

• Project/Area Number: 17K11202
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Urology
• Research Institution: Sapporo Medical University
• Principal Investigator: Tanaka Toshiaki 札幌医科大学, 医学部, 講師 (50398327)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 臓器移植 / 移植免疫 / ストレス応答 / 拒絶反応 / heat shock protein / 腎移植 / 移植片拒絶反応 / allograft / allorejection / heart transplantation / graft survival / graft perfusion / 移植片拒絶 / マウス心移植 / 移植・再生医療 / 免疫学 / ストレス

Outline of Final Research Achievements

Administration of an HSP90 inhibitor to recipients inhibit the alloimmune response and prolonged the allograft survival in murine heart transplantation. HLA class I expression was suppressed in the graft by the treatment. Furthermore, preconditioning of a graft with 17DMAG equivalently prolonged the allograft survival. Expression of IL-2 and IL-12b in the graft was suppressed, suggesting that 17DMAG preconditioning suppress the adaptive immune response, leading to inhibition of acute allograft rejection. An additional study suggested that 17DMAG preconditioning also had senolytic effect in the graft. Preconditioning of the graft targeting HSP90 may be a promising strategy in solid organ transplantation
In addition, we have collected 25 serum and urine samples from 15 kidney recipients to assess association between serum or urine HSP concentration and allograft rejection although the result has not been analyzed.

Academic Significance and Societal Importance of the Research Achievements

臓器移植における現在の課題として、ドナー不足、抗体関連型拒絶反応、免疫抑制剤による副作用などが挙げられる。HSP90を標的とした新たな免疫抑制療法の開発は、既存の免疫抑制剤の減量を可能にし、これが副作用の軽減に繋がると考えられる。また、薬剤による移植片灌流は、副作用などレシピエントへの影響が少ないものと考えられ、安全性が高いと考えられる。この処理により、高齢ドナーや高リスクドナーからの移植片の質を改善させる可能性が示されており、ドナーソースの拡大、さらには臓器移植成績の改善に寄与することが期待できる。

Research Products

• [Journal Article] 臓器移植におけるHSP90の役割 (2020)
  • Author(s): 田中 俊明
  • Journal Title: BIO Clinica Volume: 35 Pages: 65-67
• [Journal Article] In the absence of natural killer cell activation donor-specific antibody mediates chronic, but not acute, kidney allograft rejection. (2019)
  • Author(s): Yagisawa T, Tanaka T, Miyairi S, Tanabe K, Dvorina N, Yokoyama WM, Valujskikh A, Baldwin WM 3rd, Fairchild RL.
  • Journal Title: Kidney International Volume: 95 Issue: 2 Pages: 350-362
  • DOI: 10.1016/j.kint.2018.08.041
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Graft perfusion with alvespimycin, an HSP90 inhibitor, suppresses IL-2 and IL-12b production in graft-infiltrating cells, leading to prolongation of graft survival in murine heart transplantation. (2019)
  • Author(s): Tanaka T, Maehana T, Masumori N.
  • Organizer: American Transplant Congress 2019-the 19th Annual Meeting
  • Int'l Joint Research
• [Presentation] HSP90阻害剤・alvespimycinのグラフト灌流によるマウス心移植生着延長効果の機序の解析 (2019)
  • Author(s): 田中俊明、前鼻健志、舛森直哉
  • Organizer: 第55回日本移植学会
• [Presentation] Graft perfusion with alvespimycin, an HSP90 inhibitor, suppresses acute allograft rejection and prolongs graft survival in murine heart transplantation (2018)
  • Author(s): Toshiaki Tanaka
  • Organizer: American Transplant Congress 2018
  • Int'l Joint Research
• [Presentation] マウス同種心移植におけるHSP90阻害剤グラフト灌流の治療効果 (2018)
  • Author(s): 田中俊明
  • Organizer: 第54回日本移植学会