oxadiazoles and Graft-vs-Host-Disease

Sphingosine-1-phosphate (S1P), a lipid mediator, regulates lymphocyte migration between lymphoid tissue and blood. Furthermore, S1P participates in several physiological phenomena including angiogenesis, inflammation, immune regulation, and neurotransmitter release. Moreover, S1P/S1P receptor signaling involves in systemic sclerosis (SSc) pathogenesis. This study aimed to investigate whether the selective S1P

Topics: Animals; B-Lymphocytes; Cell Count; Collagen; Cytokines; Disease Models, Animal; Down-Regulation; Female; Fibroblasts; Fibrosis; Graft vs Host Disease; Male; Mice; Oxadiazoles; Propylene Glycols; RNA, Messenger; Scleroderma, Systemic; Skin; Sphingosine-1-Phosphate Receptors; T-Lymphocytes, Regulatory

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.

Topics: Animals; Bone Marrow Transplantation; Cell Movement; Chemokine CCL2; Chemokine CCL7; Disease Models, Animal; Fingolimod Hydrochloride; Gene Expression Regulation; Graft vs Host Disease; Human Umbilical Vein Endothelial Cells; Humans; Immunosuppressive Agents; Indans; Macrophages; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Monocytes; Oxadiazoles; Receptors, Lysosphingolipid; Severity of Illness Index; Signal Transduction; T-Lymphocytes; Whole-Body Irradiation