Host-derived Semaphorine-4A contributes to maintain regulatory T cell after allogeneic hematopoietic stem cell transplantation

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K08827
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Kansai Medical University
• Principal Investigator: SATAKE Atsushi 関西医科大学, 医学部, 講師 (50412028)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: セマフォリン / 制御性T細胞 / 移植片対宿主病 / 同種造血幹細胞移植

Outline of Final Research Achievements

We employed a murine acute GVHD model (B6 to BALB/c). Seven days after transplantation, the proportion of Tregs in the spleen in Sema4A-KO (KO) host mice was significantly lower than that of WT host mice. Both preexisting and inducible Tregs were decreased in KO host mice. We observed similar suppressive function between Tregs cocultured with WT and KO APCs. KO host mice developed significantly higher GVHD mortality compared to WT host mice. When bone marrow chimera mice were used as host, WT>KO host mice developed comparable GVHD mortality with WT>WT host mice, indicating that hematopoietic cell-derived Sema4A is responsible for GVHD protection. KO host mice showed comparable mortality to WT host mice when Treg-depleted graft was transplanted, suggesting that Sema4A plays an important role for Treg dependent GVHD protection. Together, these results suggest that Sema4A contributes to Treg maintenance and the regulation of alloimmune responses after allo-HCT.

Free Research Field

造血幹細胞移植学

Academic Significance and Societal Importance of the Research Achievements

これまで明らかとなっていなかった同種造血幹細胞移植の免疫応答におけるSema4Aの役割について、解明する事ができた。移植後Tregの維持にSema4Aが重要な役割を果たしている事が示唆された事で、今回の研究で得られた知見は、Sema4Aを標的とした新たな免疫抑制療法の開発を検討するための重要な基礎的データとなると考えられる。また、ホストのSema4Aを利用してGVHD発症や重症化リスクを事前に予測できる可能性もあり、個々の患者で最適なGVHD予防法や治療介入時期を選択するための情報として応用する事も期待できる。