The S 1P, receptor-selective agonist CYM-5442 reduces the severity of acute GVHD byinhibiting macrophage recruitment  

作　　者：Qiao Cheng Shoubao Ma Dandan Lin Yu Mei Huanle Gong Lei Lei Yuanyuan Chen Ye Zhao Bo Hut Yan Wu Xiao Yu Lixiang Zhao Haiyan Liu 

机构地区：[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 [2]Department of Hematology, First Affiliated Hospital of Soochow University, Suzhou, China [3]Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, First Affiliated Hospital of Soochow University, Suzhou, China

出　　处：《Cellular & Molecular Immunology》2015年第6期681-691,共11页中国免疫学杂志（英文版）

基　　金：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）.

摘　　要：FTY720, an agonist for four of the five known sphingosine- 1-phosphate （SIP） receptors, has been reported to inhibit acute graft-versus-host disease （aGVHD）. Because FTY720 functions through multiple SIP receptors, the mechanism of action through one or more of these receptors may account for its side effects. Thus, more selective SIP 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 SIPl-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 SIPl-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.FTY720, an agonist for four of the five known sphingosine- 1-phosphate （SIP） receptors, has been reported to inhibit acute graft-versus-host disease （aGVHD）. Because FTY720 functions through multiple SIP receptors, the mechanism of action through one or more of these receptors may account for its side effects. Thus, more selective SIP 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 SIPl-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 SIPl-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.

关 键 词：S 1P S 1P receptor agonist Monocyte/Macrophagel CHEMOKINE 

分 类 号：Q343[生物学—遗传学] Q593.2