Effect of ONO-4053 on Fc Epsilon RI Stimulated-Mast Cell Activation

Rationale: As prostaglandin D₂ (PGD₂), a chemical mediator released in large amounts from mast cells, is known to be involved in a number of allergic responses, blockage of PGD₂ action might be beneficial for the treatment of allergic disease.  ONO-4053 is an orally active DP1 (a PGD₂ receptor) antagonist in phase 2 clinical trial for the treatment of allergic rhinitis.  The purpose of this study was to investigate the effect of ONO-4053 on mast cell activation after Fc epsilonRI stimulation.

Methods: Human mast cells were differentiated from CD34-positive bone marrow cells in the presence of stem cell factor (SCF), IL-6 and IL-3.  After overnight sensitization with human myeloma IgE, the cells were incubated with and without ONO-4053 at 37 °C for 60 min.  Goat anti-human IgE antibody was then added to initiate the reaction, and the amounts of histamine and PGD₂ after 30 min reaction, and cytokines after 6 hours reaction were determined.

Results: ONO-4053 concentration-dependently inhibited Fc epsilonRI-stimulated histamine release and PGD₂ production in human mast cells, but did not affect cytokines production in these cells.  Other DP1 antagonists had no effect on histamine release, PGD₂ production, or cytokines production in the stimulated mast cells.

Conclusions: The findings of this study indicate that ONO-4053 would be clinically useful for a variety of allergic diseases, including allergic rhinitis, by the action of both DP1 antagonism and suppression of mast cell activation.