DP2 (CRTh2) Antagonism Reduces Ocular Inflammation Induced by Allergen Challenge and Respiratory Syncytial Virus

Abstract

Background: Allergic conjunctivitis is characterized by itchy, watery and swollen eyes which occur in response to exposure to seasonal or environmental allergens. The early phase reaction of allergic conjunctivitis is primarily mediated by mast cell degranulation while the late phase reaction is driven by Th2 cells and eosinophils. Prostaglandin D₂ (PGD₂), released from mast cells, is present in allergic conjunctival tears and may elicit classical allergic responses via interaction with the high-affinity DP2 receptor (chemoattractant receptor-homologous molecule expressed on Th2 cells, CRTh2). Furthermore, antagonism of this receptor is well known to inhibit eosinophil chemotaxis, basophil activation and Th2 cytokine production. PGD₂, therefore, may be involved in both early and late phase reactions in response to allergen challenge. Methods: Thus, we explored whether our novel and selective DP2 antagonist AM156 would be efficacious in animal models of allergic conjunctivitis. Furthermore, as respiratory syncytial virus (RSV) has been implicated in the pathogenesis of allergic conjunctivitis, we examined the effects of DP2 antagonism in a murine model of RSV ocular infection. Results: Utilizing a guinea pig ovalbumin model and a murine ragweed model we demonstrated that AM156 reduces redness, discharge and swelling in response to allergen challenge. These effects were equal to or greater than those of current clinical treatment options for allergic conjunctivitis including topical corticosteroids and a dual-mechanism antihistamine and decongestant. AM156 significantly reduced RSV-induced ocular inflammation and IL-4 production. Conclusion: These results suggest that a topical DP2 antagonist such as AM156 may represent a novel therapeutic for allergic conjunctivitis.

PGD2/DP2 receptor activation promotes severe viral bronchiolitis by suppressing IFN- λ production

“…Here, our findings suggest that IL-33 might also dampen antiviral immunity via the induction of h-PGDS expression and downstream PGD2 production. Others have shown that DP2 blockade decreases RSV-induced ocular inflammation using a mouse model of allergic conjunctivitis (41). However, the investigators did not assess viral load or elucidate the mechanism by which DP2 antagonism was protective.…”

Ocular Tropism of Respiratory Viruses

“…Bovine and sheep isolates of RSV have caused conjunctivitis with mild respiratory disease in lambs and cattle (132)(133)(134)(135), highlighting the ability of this virus to cause ocular complications in nonhuman species. Several potential approaches to mitigate ocular inflammation following RSV infection are under investigation, including anticytokine treatments and the use of protein inhibitors (27,136,137). Considering the high burden of disease associated with this virus in humans, even a low level of documented ocular disease following RSV infection indicates a public health need to better understand this property.…”

Prostaglandins and Their Receptors in Eosinophil Function and As Therapeutic Targets

“…It correlates with the severity of the disease on the one hand, and levels of PGD 2 on the other hand (78). Exogenously applied PGD 2 and DP2 agonists provoke peripheral blood eosinophilia and infiltration of eosinophils into the conjunctiva, lung, nose, and skin in animal models (30, 38, 79–82), whereas pharmacological blockade of DP2 can ameliorate models of atopic dermatitis, asthma, rhinitis, and conjunctivitis (83–88). Interestingly, DP2-deficient mice develop a normal chronic allergic inflammatory response to allergen challenge after sensitization and challenge, while the acute inflammatory response and eosinophil infiltration in the skin are abrogated (89).…”