Fevipiprant is superior to montelukast in suppressing type 2 cytokine production from mast cell stimulated human Th2 cells

Abstract

Background: Fevipiprant is a selective prostaglandin D2 receptor 2 (DP2) receptor antagonist which reduces eosinophilic airway inflammation in patients with persistent asthma and elevated sputum eosinophil counts. CD4+Th2 cells are a source of type 2 cytokines in asthma, via DP2 and leukotriene (LT) pathway activation. Aim: To compare fevipiprant with montelukast for suppression of type 2 cytokine and other inflammatory mediator production from human Th2 cells in the presence of endogenous stimuli of DP2 and LT pathways from activated mast cell (MC) supernatants. Methods: CD4+ T cells were isolated from healthy volunteers (HV), differentiated with IL-2/IL-4, sorted for DP2 expression and stimulated with MC supernatants in presence or absence of fevipiprant (1 µM) or montelukast (1 µM). mRNA was isolated and RT-PCR conducted on cytokines. MCs were CD34+ precursor cells from HV, differentiated and stimulated with IgE/anti-IgE in the presence or absence of cPLA2 inhibitor ZPL521 (20 µM) as positive control. Results: MC supernatants induced substantial activation of human DP2+ Th2 cells as suggested by increases in mRNA expression of IL-5 and IL-13. These increases were fully suppressed by fevipiprant, but not by montelukast, which only gave partial (~ 40%) reduction of IL-5 and IL-13 expression. Similar differences between drugs were found for suppression of increases in IL-3, IL-4, IL-8, M-CSF and GM-CSF mRNA expression. Conclusion: Consistent with the greater amplitude of inflammation induced by the DP2 pathway compared to the LT pathway, fevipiprant is superior to montelukast in suppressing type 2 and other inflammatory cytokine production in human MC-stimulated Th2 cells.