Development of a novel algorithm for immune regulation that enables the active Treg amplification soon after HSCT

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K09954
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Okayama University
• Principal Investigator: Matsuoka Ken-ichi 岡山大学, 医歯薬学総合研究科, 准教授 (90432640)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 造血幹細胞移植 / 移植片対宿主病 / 制御性T細胞

Outline of Final Research Achievements

In this study, we investigated the immune control algorithm after PTCy-based transplantation. Using a tumor-bearing murine BMT system that models clinical transplantation, we demonstrated that (1) graft-versus-leukemia effect can be enhanced by PTCy reduction, and (2) reduced GVHD suppressive activity after PTCy reduction is compensated by active Treg amplification by NKT ligand administration. Furthermore, cellular immunological and gene-expression analysis clarified that administration of the ligand efficiently promote differentiation into tolerogeneic NKT2 phenotype while suppressing differentiation into proinflammatory NK-like-NKT1 phenotype, which could promote Treg amplification. .These results indicate that the combination of PTCy and NKT-ligand therapy could provide a novel immunoadjuvant therapy to optimize PTCy transplantation, especially in patients at potential risk of disease relapse.

Free Research Field

血液内科学　造血幹細胞移植学

Academic Significance and Societal Importance of the Research Achievements

移植後シクロフォスファミド法（PTCy法）は、HLA半合致移植においても効率的な急性GVHD予防を可能とし、今後はHLA適合移植にもその適用が拡大すると考えられる。この一方で、低い移植関連合併症に比して、特に非寛解患者における移植後再発が懸念されている。今回われわれは、特に再発リスクのある患者のPTCy移植の最適化を臨床的命題として検討し、PTCy減量およびPTCy後のアンジュバント投与によって、超急性期からのTreg増幅を基盤としてGVHD/GVLバランスを変容させ、患者個別的に調整できる可能性を実験的に示した。今後の移植適応の拡大、安全性の向上に資する基礎的知見となると考えられる。