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The S1P1 receptor-selective agonist CYM-5442 reduces the severity of acute GVHD by inhibiting macrophage recruitment

Cellular & Molecular Immunology volume 12, pages 681–691 (2015)Cite this article

Abstract

FTY720, an agonist for four of the five known sphingosine-1-phosphate (S1P) receptors, has been reported to inhibit acute graft-versus-host disease (aGVHD). Because FTY720 functions through multiple S1P receptors, the mechanism of action through one or more of these receptors may account for its side effects. Thus, more selective S1P receptor modulators are needed to evaluate the roles of different S1P receptors and their therapeutic efficacies. In this study, we investigated the effect of an S1P1-selective agonist, CYM-5442, on the progression of aGVHD. We showed that CYM-5442 significantly inhibited but did not prevent aGVHD. CYM-5442 did not affect the infiltration of the donor T cells into the target organs, while the number of macrophages in GVHD organs was significantly reduced by CYM-5442 treatment. In vivo proliferation assays showed that the proliferation of macrophages was not suppressed by CYM-5442. Further studies using human endothelial cells demonstrated that CYM-5442 treatment downregulated CCL2 and CCL7 expression in endothelial cells, therefore reducing the migration of monocytes, from which tissue macrophages originate. Our data demonstrate the therapeutic efficacy of an S1P1-selective agonist in aGVHD and its possible mechanism of action. The results suggest that further investigations are needed regarding CYM-5442 as a potential therapeutic regimen for aGVHD.

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Acknowledgements

This work has been supported by the grants from the National Natural Science Foundation of China (91029703, 81072436 and 81273268), with project funding from Suzhou City (SWG0904, SZS201109), Priority Academic Program Development of Jiangsu Higher Education Institutions, Qing Lan Project of Jiangsu Province, Jiangsu Provincial Innovative Research Team and the Program for Changjiang Scholars and Innovative Research Team in University (IRT1075).

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  1. Dr HY Liu, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China. E-mail: hliu@suda.edu.cn

Authors and Affiliations

  1. Laboratory of Cellular and Molecular Tumor Immunology, Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China

    Qiao Cheng, Shoubao Ma, Dandan Lin, Yu Mei, Huanle Gong, Lei Lei, Yuanyuan Chen, Ye Zhao, Bo Hu, Yan Wu, Xiao Yu, Lixiang Zhao & Haiyan Liu

  2. Department of Hematology, First Affiliated Hospital of Soochow University, Suzhou, China

    Ye Zhao

  3. Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, First Affiliated Hospital of Soochow University, Suzhou, China

    Haiyan Liu

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Cheng, Q., Ma, S., Lin, D. et al. The S1P1 receptor-selective agonist CYM-5442 reduces the severity of acute GVHD by inhibiting macrophage recruitment. Cell Mol Immunol 12, 681–691 (2015). https://doi.org/10.1038/cmi.2014.59

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