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STEM CELL TRANSPLANTATION

Dimethyl fumarate ameliorates chronic graft-versus-host disease by inhibiting Tfh differentiation via Nrf2

Leukemia volume 39, pages 473–481 (2025)Cite this article

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Abstract

Chronic graft-versus-host disease (cGVHD), characterized by chronic tissue inflammation and fibrosis involving multiple organs, remains a major complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Dimethyl fumarate (DMF) is an anti-inflammatory drug approved for the treatment of multiple sclerosis and psoriasis. We previously reported that DMF effectively inhibits acute GVHD (aGVHD) while preserving the graft-versus-leukemia effect. However, the role of DMF in cGVHD progression remains unknown. Here, we found that DMF administration significantly suppresses follicular helper T cell (Tfh) differentiation, and germinal center formation and alleviates disease severity in different murine cGVHD models. Mechanistically, DMF treatment downregulates IL-21 transcription by activation of Nrf2, thus orchestrating Tfh-related gene programs both in mice and humans. The inhibitory role of DMF on Tfh cell differentiation was diminished in Nrf2 deficient T cells. Importantly, the therapeutic potential of DMF in clinical cGVHD has been validated in human data whereby DMF effectively reduces IL-21 production and Tfh cell generation in peripheral blood mononuclear cells from active cGVHD patients and further attenuates xenograft GVHD. Collectively, our findings reveal that DMF potently inhibits cGVHD development by repressing Tfh cell differentiation via Nrf2, paving the way for the treatment of cGVHD in the clinic.

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Fig. 1: DMF alleviates the development of murine scleroderma-like cGVHD.
Fig. 2: DMF inhibits pathogenic T cell differentiation and GC response in scleroderma-like cGVHD.
Fig. 3: DMF attenuates lupus-like cGVHD by inhibiting Tfh and GC B cells.
Fig. 4: DMF inhibits Tfh cell differentiation and orchestrates the transcriptional profiles.
Fig. 5: DMF inhibits IL-21 production in a Nrf2-dependent manner.
Fig. 6: Immunologic effects of DMF on human cGVHD.

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This paper does not report original code. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

Code availability

This paper does not report original code. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

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Acknowledgements

This work was supported by the National Key R&D Program of China (2022YFC2502700), National Natural Science Foundation of China (No. 81974001, 82170222, 81900180, 82060035, 82300250, 82370215, 82330008, 82460047, and 82020108003), Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), Jiangsu Province Capability Improvement Project through Science, Technology and Education (CXZX202201), the Jiangsu Social Development Program (BE2018651), Natural Science Foundation of Jiangsu Province (BK20211070, BK20220246, BK20240354), Suzhou Science and Technology Program Project (SLT201911, SKY2021039, SKY2022132, SSD2024037 and SKY2023047) and Translational Research Grant of NCRCH (2021ZKQC01, 2021ZKQC02). We thank Dr. Zhian Chen from the University of Queensland for his valuable suggestions.

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Author notes

  1. These authors contributed equally: Fulian Lyu, Huanle Gong, Xiaojin Wu, Xin Liu, Yinghao Lu.

Authors and Affiliations

  1. National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China

    Fulian Lyu, Huanle Gong, Xiaojin Wu, Xin Liu, Xiya Wei, Chenchen Liu, Yaoyao Shen, Yuhang Wang, Lei Lei, Jia Chen, JingJing Han, Yang Xu & Depei Wu

  2. Key Laboratory of Stem Cells and Biomedical Materials of Jiangsu Province and Chinese Ministry of Science and Technology, Suzhou, China

    Fulian Lyu, Huanle Gong, Xiaojin Wu, Xin Liu, Yaoyao Shen, Lei Lei, Jia Chen, JingJing Han, Yang Xu & Depei Wu

  3. Department of Hematology, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China

    Yinghao Lu

  4. Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, USA

    Shoubao Ma

  5. Frazer Institute, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia

    Hongjian Sun & Di Yu

  6. Ian Frazer Centre for Children’s Immunotherapy Research, Child Health Research Centre, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia

    Di Yu

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Contributions

HG, JH, YX and DW designed the study and supervised the research. FL, HG, XW, XL and YL performed the experiments and analyses. XW, CL, YW, LL and JC contributed to the experiments. SM, HS and DY analyzed the sequencing data and provided expertise. SM, FL, JH, HG, YX and DW wrote, edited, and reviewed the manuscript. All authors have read and approved the article.

Corresponding authors

Correspondence to Huanle Gong, JingJing Han, Yang Xu or Depei Wu.

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All patient samples and additional clinical information used in this study were collected by the First Affiliated Hospital of Soochow University with informed consent from all patients. This study was approved by the Medical Ethics Committee of the First Affiliated Hospital of Soochow University (2024639) in accordance with the Declaration of Helsinki.

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Lyu, F., Gong, H., Wu, X. et al. Dimethyl fumarate ameliorates chronic graft-versus-host disease by inhibiting Tfh differentiation via Nrf2. Leukemia 39, 473–481 (2025). https://doi.org/10.1038/s41375-024-02475-5

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