DBY/HLA class II complex formation on the vascular endothelium leads to cGVHD in female-to-male HSCT

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K17841
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Jichi Medical University
• Principal Investigator: Morita Kaoru 自治医科大学, 医学部, 助教 (20813223)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 慢性GVHD / DBY / HLA class II / ネオセルフ / 同種抗体

Outline of Final Research Achievements

Development of effective treatments for cGVHD has been hindered by the complexities of its pathogenesis. Among several risk factors, the presence of allogeneic antibodies against DBY encoded on Y chromosome is well described and associated with NRM in female-to-male transplants. However, DBY is expressed exclusively in testis, and how DBY is emerged on the surface of the target organs remains unknown. Here we report that DBY/HLA class II complex formation on the vascular endothelium directly contribute to the pathogenesis. Full-length DBY is transported to the cell surface only via association with HLA class II. The seropositivity of IgG against this complex was significantly associated with cGVHD development. Moreover, DBY specifically colocalized with HLA class II on the dermal vascular endothelial cells in cGVHD. Finally, we revealed that the efficacy of DBY presentation by each HLA-DR allele was correlated with that allele on susceptibility to cGVHD using nationwide registry data.

Free Research Field

慢性GVHD

Academic Significance and Societal Importance of the Research Achievements

適切なマウスモデルがいないこともあり、慢性GVHDの病態は不明な点が多く、新規薬剤でも寛解に達する人はほとんどいないのが現状である。本研究では慢性GVHDの初期の標的細胞を同定するために同種抗体に着目し、血管内皮細胞が重要な標的の一つであることを明らかにした。異常な同種・自己抗体の出現は異性間移植以外にも報告されており、本研究の成果は、今後の慢性GVHD全体の病態理解につながると確信する。