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

• 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
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2020: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2019: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 慢性GVHD / DBY / HLA class II / ネオセルフ / 同種抗体 / H-Y抗原/MHCクラスII複合体 / 同種移植 / 同種抗原/MHCクラスII複合体 / H-Y蛋白質/MHC class II複合体 / フローサイトメトリー / 免疫沈降 / MHCクラスII / CMV

Outline of Research at the Start

同種造血幹細胞移植は造血器腫瘍に対する最も強力な治療法である。しかし, 移植の主たる合併症である慢性移植片対宿主病(cGVHD)は, 自己免疫疾患様の症状を呈し, 治療が困難なため, 新たな治療法開発が急務である。私たちは女性ドナーから男性レシピエントへの移植で, Y染色体の蛋白質に対する同種抗体の存在量がcGVHDの発症に強く相関することを報告した。本研究ではcGVHDの根本治療を最終目標として, cGVHDの病因である同種抗体の産生機構の解明を目的とする。本研究の成果は, 同種抗体産生の新たな機構を解明するとともに, 液性免疫の制御を介したcGVHDの新たな治療戦略の開発に繋がる。

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.

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。

Research Products

• [Journal Article] Dimethyl fumarate ameliorates graft‐versus‐host disease by inhibiting T‐cell metabolism and immune responses through a reactive oxygen species‐dependent mechanism (2022)
  • Author(s): Mashima Kiyomi、Sato Kazuya、Ikeda Takashi、Izawa Junko、Takayama Norihito、Hayakawa Hiroko、Kawaguchi Shin‐Ichiro、Nakano Hirofumi、Nagayama Takashi、Umino Kento、Morita Kaoru、Tominaga Kaoru、Endo Hitoshi、Kanda Yoshinobu
  • Journal Title: British Journal of Haematology Volume: 00 Issue: 6 Pages: 1-5
  • DOI: 10.1111/bjh.18082
  • Peer Reviewed
• [Journal Article] Identification of endoscopic factors that predict poor responses to steroids in patients with gastrointestinal acute graft-versus-host disease (2021)
  • Author(s): Morita Kaoru、Fujiwara Shin-ichiro、Ikeda Takashi、Kawaguchi Shin-ichiro、Toda Yumiko、Ito Shoko、Nagayama Takashi、Mashima Kiyomi、Umino Kento、Minakata Daisuke、Nakano Hirofumi、Yamasaki Ryoko、Ashizawa Masahiro、Yamamoto Chihiro、Hatano Kaoru、Sato Kazuya、Oh Iekuni、Ohmine Ken、Kanda Yoshinobu
  • Journal Title: Bone Marrow Transplantation Volume: 56 Issue: 4 Pages: 963-967
  • DOI: 10.1038/s41409-020-01096-7
  • Peer Reviewed / Open Access
• [Journal Article] Mesenchymal stromal cells inhibit aerobic glycolysis in activated T-cells by negatively regulating hexokinase II activity through PD-1/PD-L1 interaction. (2021)
  • Author(s): Kawasaki, Y., Sato, K., Mashima, K., Nakano, H., Ikeda, T., Umino, K., Morita, K., Izawa, J., Takayama, N., Hayakawa, H., Tominaga, K., Endo, H., Kanda, Y.
  • Journal Title: Biology of Blood and Marrow Transplantation Volume: 27 Issue: 3 Pages: 231.e1-231.e8
  • DOI: 10.1016/j.jtct.2020.11.012
  • Peer Reviewed / Open Access
• [Journal Article] Comparison of alemtuzumab, anti-thymocyte globulin, and post-transplant cyclophosphamide for graft-versus-host disease and graft-versus-leukemia in murine models (2021)
  • Author(s): Mashima Kiyomi、Oh Iekuni、Fujiwara Ken、Izawa Junko、Takayama Norihito、Nakano Hirofumi、Kawasaki Yasufumi、Minakata Daisuke、Yamasaki Ryoko、Morita Kaoru、Ashizawa Masahiro、Yamamoto Chihiro、Hatano Kaoru、Sato Kazuya、Ohmine Ken、Fujiwara Shin-Ichiro、Ohno Nobuhiko、Kanda Yoshinobu
  • Journal Title: PLOS ONE Volume: 16 Issue: 1 Pages: 1-14
  • DOI: 10.1371/journal.pone.0245232
  • Peer Reviewed / Open Access