title: The S1P1 receptor-selective agonist CYM-5442 reduces the severity of acute GVHD by inhibiting macrophage recruitment.
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.
authors.affiliation: Laboratory of Cellular and Molecular Tumor Immunology, Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
authors.forename: Qiao
authors.initials: Q
authors.lastname: Cheng
authors.affiliation: Laboratory of Cellular and Molecular Tumor Immunology, Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
authors.forename: Shoubao
authors.initials: S
authors.lastname: Ma
authors.affiliation: Laboratory of Cellular and Molecular Tumor Immunology, Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
authors.forename: Dandan
authors.initials: D
authors.lastname: Lin
authors.affiliation: Laboratory of Cellular and Molecular Tumor Immunology, Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Mei
authors.affiliation: Laboratory of Cellular and Molecular Tumor Immunology, Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
authors.forename: Huanle
authors.initials: H
authors.lastname: Gong
authors.affiliation: Laboratory of Cellular and Molecular Tumor Immunology, Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Lei
authors.affiliation: Laboratory of Cellular and Molecular Tumor Immunology, Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Laboratory of Cellular and Molecular Tumor Immunology, Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.|Department of Hematology, First Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Laboratory of Cellular and Molecular Tumor Immunology, Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Hu
authors.affiliation: Laboratory of Cellular and Molecular Tumor Immunology, Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Laboratory of Cellular and Molecular Tumor Immunology, Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Yu
authors.affiliation: Laboratory of Cellular and Molecular Tumor Immunology, Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
authors.forename: Lixiang
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Laboratory of Cellular and Molecular Tumor Immunology, Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.|Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, First Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Liu
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D002465:Cell Movement / Q000187:drug effects; D018932:Chemokine CCL2 / Q000235:genetics / Q000276:immunology; D054410:Chemokine CCL7 / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D000068876:Fingolimod Hydrochloride / Q000494:pharmacology; D005786:Gene Expression Regulation; D006086:Graft vs Host Disease / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007189:Indans / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D010069:Oxadiazoles / Q000494:pharmacology*; D049349:Receptors, Lysosphingolipid / Q000819:agonists* / Q000235:genetics / Q000276:immunology; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D014916:Whole-Body Irradiation
chemical_list: C532995:2-(4-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl amino)ethanol; C111835:CCL2 protein, human; C515450:CCL7 protein, human; D018932:Chemokine CCL2; D054410:Chemokine CCL7; D007166:Immunosuppressive Agents; D007189:Indans; D010069:Oxadiazoles; D049349:Receptors, Lysosphingolipid; D000068876:Fingolimod Hydrochloride
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