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 S1P 1 -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 S1P 1 -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.

An update on sphingosine-1-phosphate receptor 1 modulators

“…122 CYM5442 was also found to retard but not prevent acute graft- versus -host disease (aGVHD) through reduction of macrophage infiltration in mice. 123 A close derivative of CYM5442 is compound RP-001, featuring a carboxylic acid instead of the terminal alcohol of CYM5442 as well as isopropoxy and nitrile substituents at the aromatics instead of two former ethoxy moieties. S1P 1 agonism of RP-001 proved to be highly potent with an EC 50 value of 9 pM; S1P 2–4 activity is reported to be low, S1P 5 agonism is considered moderate.…”

Successful treatment with fingolimod of graft-versus-host disease of the central nervous system

“…1,2 Targeting lymphocyte trafficking with sphingosine-1-phosphate receptors (S1PR) agonists is a promising approach to treat GVHD, which have proven efficient in several preclinical models. 3,4 Here, we describe the case of a 66-year-old patient with severe CNS GVHD treated successfully with fingolimod (FTY720), a first-in-class, orally bioavailable S1PR agonist approved by the US Food and Drug Administration in 2010 for the treatment of relapsing forms of multiple sclerosis (MS).…”

STAT3 Expression in Host Myeloid Cells Controls Graft-versus-Host Disease Severity

“…For example, host MFs survive BMT conditioning, modulate donor T cell functions 14 , infiltrate GVHD target organs 10, 11 , and inhibiting their ability to migrate to GVHD target organs ameliorates GVHD 12 . In addition, dexamethasone ameliorates GVHD by reducing production of pro-inflammatory cytokines from host derived MFs 13 , while decreasing the number of host MFs enhances donor T cell expansion and aggravates acute GVHD 15 .…”

“…But the effect of macrophages (MFs), another type of APC which infiltrate GVHD target organs 10, 11 on GVHD is less well-understood. In support of a role for MFs influencing GVHD, acute GVHD was reduced when macrophage recruitment to GVHD target organs was inhibited by CYM-5442, a sphingosine 1-phosphate 1(S1P1) receptor agonist 12 , and the anti-GVHD properties of corticosteroids are likely due in part to inhibition of MF functions 13 . However, these studies did not distinguish the role of donor versus recipient-derived MFs on acute GVHD, which is important because both host and donor MFs are present early post allo-HCT due to the resistance of host MFs to transplant conditioning regimens 14 .…”