Inhibition of allergen-induced dermal eosinophilia by an oxoeicosanoid receptor antagonist in non-human primates

5-Oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE), acting via the OXE receptor, is unique among 5-lipoxygenase products in its ability to directly induce human eosinophil migration, suggesting its involvement in eosinophilic diseases. To address this hypothesis, we synthesized selective indole-based OXE receptor antagonists. Because rodents lack an OXE receptor orthologue, we sought to determine whether these antagonists could attenuate allergen-induced skin eosinophilia in sensitized monkeys. Experimental approach: In a pilot study, cynomolgus monkeys with environmentally acquired sensitivity to Ascaris suum were treated orally with the "first-generation" OXE antagonist 230 prior to intradermal injection of 5-oxo-ETE or Ascaris extract. Eosinophils were evaluated in punch biopsy samples taken 6 or 24 hr later. We subsequently treated captive-bred rhesus monkeys sensitized to house dust mite (HDM) allergen with a more recently developed OXE antagonist, S-Y048, and evaluated its effects on dermal eosinophilia induced by either 5-oxo-ETE or HDM. Key

5-Oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE), acting via the OXE receptor, is unique among 5-lipoxygenase products in its ability to directly induce human eosinophil migration, suggesting its involvement in eosinophilic diseases. To address this hypothesis, we synthesized selective indole-based OXE receptor antagonists. Because rodents lack an OXE receptor orthologue, we sought to determine whether these antagonists could attenuate allergen-induced skin eosinophilia in sensitized monkeys. Experimental approach: In a pilot study, cynomolgus monkeys with environmentally acquired sensitivity to Ascaris suum were treated orally with the "first-generation" OXE antagonist 230 prior to intradermal injection of 5-oxo-ETE or Ascaris extract. Eosinophils were evaluated in punch biopsy samples taken 6 or 24 hr later. We subsequently treated captive-bred rhesus monkeys sensitized to house dust mite (HDM) allergen with a more recently developed OXE antagonist, S-Y048, and evaluated its effects on dermal eosinophilia induced by either 5-oxo-ETE or HDM. Key

In a pilot experiment, both 5-oxo-ETE and Ascaris extract induced dermal eosinophilia in cynomolgus monkeys, which appeared to be reduced by 230. Subsequently, we found that the related OXE antagonist S-Y048 is a highly potent inhibitor of 5-oxo-ETE-induced activation of rhesus monkey eosinophils in vitro and has a half-life in plasma of about 6 hr after oral administration. S-Y048 significantly inhibited eosinophil infiltration into the skin in response to both intradermally administered 5-oxo-ETE and HDM. Conclusions and implications: 5-Oxo-ETE may play an important role in allergen-induced eosinophilia. Blocking its effects with S-Y048 may provide a novel therapeutic approach for eosinophilic diseases.