Immunological activation of mast cells is an important trigger in the cascade of inflammatory events leading to the manifestation of allergic diseases. Pharmacological studies using the recently discovered DP(1) and CRTH2 antagonists combined with genetic analysis support the view that these receptors have a pivotal role in mediating aspects of allergic diseases that are resistant to current therapy. This Review focuses on the emerging roles that DP(1) and CRTH2 (also known as DP(2)) have in acute and chronic aspects of allergic diseases and proposes that, rather than having opposing actions, these receptors have complementary roles in the initiation and maintenance of the allergy state. We also discuss recent progress in the discovery and development of selective antagonists of these receptors.
PGD2, produced by mast cells, has been detected in high concentrations at sites of allergic inflammation. It can stimulate vascular and other inflammatory responses by interaction with D prostanoid receptor (DP) and chemoattractant receptor-like molecule expressed on Th2 cells (CRTH2) receptors. A significant role for PGD2 in mediating allergic responses has been suggested based on the observation that enhanced eosinophilic lung inflammation and cytokine production is apparent in the allergen-challenged airways of transgenic mice overexpressing human PGD2 synthase, and PGD2 can enhance Th2 cytokine production in vitro from CD3/CD28-costimulated Th2 cells. In the present study, we investigated whether PGD2 has the ability to stimulate Th2 cytokine production in the absence of costimulation. At concentrations found at sites of allergic inflammation, PGD2 preferentially elicited the production of IL-4, IL-5, and IL-13 by human Th2 cells in a dose-dependent manner without affecting the level of the anti-inflammatory cytokine IL-10. Gene transcription peaked within 2 h, and protein release peaked ∼8 h after stimulation. The effect of PGD2 was mimicked by the selective CRTH2 agonist 13,14-dihydro-15-keto-PGD2 but not by the selective DP agonist BW245C, suggesting that the stimulation is mediated by CRTH2 and not DP. Ramatroban, a dual CRTH2/thromboxane-like prostanoid receptor antagonist, markedly inhibited Th2 cytokine production induced by PGD2, while the selective thromboxane-like prostanoid receptor antagonist SQ29548 was without effect. These data suggest that PGD2 preferentially up-regulates proinflammatory cytokine production in human Th2 cells through a CRTH2-dependent mechanism in the absence of any other costimulation and highlight the potential utility of CRTH2 antagonists in the treatment of allergic diseases.
This study provides the first clinical evidence that CRTH2 receptors contribute to airflow limitation, symptoms and eosinophilic airway inflammation in asthma. OC000459 shows promise as a novel oral treatment for asthma and related disorders.
Prostaglandin D 2 (PGD 2 ) is produced by mast cells, Th2 lymphocytes and dendritic cells and has been detected in high concentrations at sites of allergic inflammation. PGD 2 exerts its inflammatory effects through high affinity interactions with the G protein coupled receptors DP 1 and chemoattractant-homologous receptor expressed on Th2 cells (CRTH2, also known as DP 2 ). DP 1 and CRTH2 act in concert to promote a number of biological effects associated with the development and maintenance of the allergic response. During the process of allergen sensitization, DP 1 activation may enhance polarization of Th0 cells to Th2 cells by inhibiting production of interleukin 12 by dendritic cells. Upon exposure to allergen in sensitized individuals, activation of DP 1 may contribute to the long lasting blood flow changes in the target organ. CRTH2 is expressed by Th2 lymphocytes, eosinophils and basophils and may mediate the recruitment of these cell types during the late phase allergic response. The role played by CRTH2 in promoting the production of Th2 cytokines and IgE make antagonism of this receptor a particularly attractive approach to the treatment of chronic allergic disease.
An 8-week treatment with the CRTH2-antagonist, OC000459, exerts modest, but significant, anti-eosinophil and beneficial clinical effects in adult patients with active, corticosteroid-dependent or corticosteroid-refractory EoE and is well tolerated.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.