Development of novel immunosuppressive method using MEK inhibitor to construct optimal environment for pancreatic islet transplantation

• Project/Area Number: 18K08593
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55010:General surgery and pediatric surgery-related
• Research Institution: Kyoto University
• Principal Investigator: Anazawa Takayuki 京都大学, 医学研究科, 助教 (90566811)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 膵島移植 / 細胞移植 / 免疫抑制 / 再生医療 / 糖尿病 / 免疫抑制剤 / 皮下移植

Outline of Final Research Achievements

The purpose of this research to investigated the utility of the mitogen-activated protein kinase inhibitor trametinib in islet transplantation. Islets from fully major histocompatibility complex-mismatched BALB/c mice were transplanted into streptozotocin-induced diabetic C57BL/6 mice via the portal vein. Trametinib prolonged graft survival significantly when compared with vehicle. Histologic analyses revealed that cellular infiltration of the graft by lymphocytes was inhibited significantly. In addition, trametinib suppressed functional differentiation of naive CD4+ T cells in recipients. Expression of mRNA encoding inflammatory cytokines in recipients treated with trametinib was also inhibited. Trametinib delayed islet graft rejection by inhibiting functional differentiation of naive CD4+ T cells and regulating inflammatory cytokines. Trametinib might be a promising candidate for immunosuppressive therapy after allogeneic islet transplantation.

Academic Significance and Societal Importance of the Research Achievements

細胞移植である膵島移植の更なる成績改善には、少ない膵島細胞でも血糖コントロールを可能とするような移植環境の構築が必要で、臓器移植と同様のプロトコールではなく、副作用のない薬剤によるAllo反応性免疫応答の制御が必要である。今回、MEK阻害剤によるAllo反応性T細胞の抑制が膵島移植にも応用可能であることが示され、新たな免疫抑制療法の選択肢となる可能性が示唆された。MEK/ERK経路の阻害はインスリン抵抗性改善効果も有するためこの薬剤は膵島移植において理想的な薬剤となりうる。同種膵島移植ならびに細胞移植におけるMEK阻害剤の免疫抑制作用については初の報告であり、他の分野にも波及しうる結果である。

Research Products

• [Journal Article] The MEK Inhibitor Trametinib Suppresses Major Histocompatibility Antigen-mismatched Rejection Following Pancreatic Islet Transplantation (2020)
  • Author(s): Seiichiro Tada, Takayuki Anazawa et al.
  • Journal Title: Transplantation Direct Volume: 6 Issue: 9 Pages: e591-e591
  • DOI: 10.1097/txd.0000000000001045
  • Peer Reviewed / Open Access
• [Journal Article] Current state and future evolution of pancreatic islet transplantation (2018)
  • Author(s): Anazawa Takayuki、Okajima Hideaki、Masui Toshihiko、Uemoto Shinji
  • Journal Title: Annals of Gastroenterological Surgery Volume: 3 Issue: 1 Pages: 34-42
  • DOI: 10.1002/ags3.12214
  • Peer Reviewed / Open Access
• [Presentation] Islet Transplantation in Japan (2021)
  • Author(s): Takayuki Anazawa
  • Organizer: The 2nd Congress of Asian Pancreas and Islet Transplant Association Pancreas and islet transplantation
  • Int'l Joint Research
• [Presentation] Efficacy and safety of islet transplantation in patients with type 1 diabetes:a Japanese single center experience (2020)
  • Author(s): Takayuki Anazawa, et al.
  • Organizer: 28th International Congress of The Transplantation Society
  • Int'l Joint Research
• [Presentation] 膵島移植における新たな作用機序による免疫抑制療法の開発と今後の展望 (2019)
  • Author(s): 多田誠一郎、穴澤貴行、他
  • Organizer: 第119回日本外科学会定期学術集会
• [Presentation] Establishment of islet allograft acceptance by mitogen-activated protein kinase kinase via suppression of alloreactive T cells (2019)
  • Author(s): Seiichiro Tada, Takayuki Anazawa
  • Organizer: 17th World Congress of the International Pancreas & Islet Transplant Association
  • Int'l Joint Research
• [Presentation] MEK阻害剤トラメチニブはMHC不適合マウス膵島移植で膵島毒性を示すことなく拒絶反応を抑制する (2019)
  • Author(s): 多田誠一郎、穴澤貴行、他
  • Organizer: 第28回日本組織適合性学会大会
• [Presentation] 膵島移植におけるMEK阻害剤の可能性 (2019)
  • Author(s): 多田誠一郎、穴澤貴行、他
  • Organizer: 第55回日本移植学会総会
• [Presentation] 膵島移植における新たな作用機序による免疫抑制療法の開発：MEK阻害剤の応用可能性 (2019)
  • Author(s): 多田誠一郎、穴澤貴行、他
  • Organizer: 第46回日本膵膵島移植研究会
• [Presentation] レシピエントの免疫応答が血管床誘導による皮下膵島移植に与える影響 (2018)
  • Author(s): 多田誠一郎、穴澤貴行、他
  • Organizer: 第54回日本移植学会総会
• [Presentation] 血管床の誘導が皮下膵島移植に与える免疫学的な影響因子の検討 (2018)
  • Author(s): 多田誠一郎、穴澤貴行、他
  • Organizer: 第45回日本臓器保存生物医学会
• [Presentation] A simple and promising strategy for pancreatic islet preconditioning to reduce immunogenicity and improve islet graft longevity (2018)
  • Author(s): Takayuki Anazawa, et al.
  • Organizer: 27th International Congress of the transplantation society
  • Int'l Joint Research