Development of novel immunosuppressive method using MEK inhibitor to construct optimal environment for pancreatic islet transplantation
| Project/Area Number |
18K08593
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 55010:General surgery and pediatric surgery-related
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| Research Institution | Kyoto University |
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Principal Investigator |
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥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)
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| 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 |
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| 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.
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| 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。
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Report
(4 results)
Research Products
(12 results)
