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

Fulian Lyu; Huanle Gong; Xiaojin Wu; Xin Liu; Yinghao Lu; Xiya Wei; Chenchen Liu; Yaoyao Shen; Yuhang Wang; Lei Lei; Jia Chen; Shoubao Ma; Hongjian Sun; Di Yu; JingJing Han; Yang Xu; Depei Wu

doi:10.1038/s41375-024-02475-5

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

Leukemia. 2024 Nov 23. doi: 10.1038/s41375-024-02475-5. Online ahead of print.

Authors

Fulian Lyu^#^{1

2}, Huanle Gong^#^{3

4}, Xiaojin Wu^#^{1

2}, Xin Liu^#^{1

2}, Yinghao Lu^#⁵, Xiya Wei¹, Chenchen Liu¹, Yaoyao Shen^{1

2}, Yuhang Wang¹, Lei Lei^{1

2}, Jia Chen^{1

2}, Shoubao Ma⁶, Hongjian Sun⁷, Di Yu^{7

8}, JingJing Han^{9

10}, Yang Xu^{11

12}, Depei Wu^{13

14}

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.
² Key Laboratory of Stem Cells and Biomedical Materials of Jiangsu Province and Chinese Ministry of Science and Technology, Suzhou, China.
³ 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. happy_kung@163.com.
⁴ Key Laboratory of Stem Cells and Biomedical Materials of Jiangsu Province and Chinese Ministry of Science and Technology, Suzhou, China. happy_kung@163.com.
⁵ Department of Hematology, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China.
⁶ Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, USA.
⁷ Frazer Institute, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.
⁸ Ian Frazer Centre for Children's Immunotherapy Research, Child Health Research Centre, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.
⁹ 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. hanjingjing@suda.edu.cn.
¹⁰ Key Laboratory of Stem Cells and Biomedical Materials of Jiangsu Province and Chinese Ministry of Science and Technology, Suzhou, China. hanjingjing@suda.edu.cn.
¹¹ 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. yangxu@suda.edu.cn.
¹² Key Laboratory of Stem Cells and Biomedical Materials of Jiangsu Province and Chinese Ministry of Science and Technology, Suzhou, China. yangxu@suda.edu.cn.
¹³ 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. drwudepei@163.com.
¹⁴ Key Laboratory of Stem Cells and Biomedical Materials of Jiangsu Province and Chinese Ministry of Science and Technology, Suzhou, China. drwudepei@163.com.

^# Contributed equally.

PMID: 39580582
DOI: 10.1038/s41375-024-02475-5

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.