Accumulation of CRTH2-positive leukocytes in human allergic nasal mucosa

Shirasaki, Hideaki; Kikuchi, Megumi; Kanaizumi, Etsuko; Himi, Tetsuo

doi:10.1016/s1081-1206(10)60239-6

Cited by 32 publications

(26 citation statements)

References 22 publications

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“…Indirect evidence is derived from the findings that the ligand PGD 2 is present in the nasal lavage fluid of patients with allergic rhinitis in response to allergen challenge (Naclerio et al, 1983;Miadonna et al, 1999) and DP2 expression is increased in allergic human nasal mucosa relative to nonallergic mucosa (Shirasaki et al, 2009). In Japan, ramatroban (Bayans), a dual DP2/TP antagonist, is clinically used for the treatment of allergic rhinitis.…”

Section: Discussionmentioning

confidence: 99%

Pharmacology of AM211, a Potent and Selective Prostaglandin D₂Receptor Type 2 Antagonist That Is Active in Animal Models of Allergic Inflammation

Bain¹,

Lorrain²,

Stebbins³

et al. 2011

J Pharmacol Exp Ther

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The prostaglandin D 2 (PGD 2 ) receptor type 2 (DP2) is a G protein-coupled receptor that has been shown to be involved in a variety of allergic diseases, including allergic rhinitis, asthma, and atopic dermatitis. In this study, we describe the preclinical pharmacological and pharmacokinetic properties of the smallmolecule DP2 antagonist [2Ј-(3-benzyl-1-ethyl-ureidomethyl)-6-methoxy-4Ј-trifluoromethyl-biphenyl-3-yl]-acetic acid (AM211). We determine that AM211 has high affinity for human, mouse, rat, and guinea pig DP2 and it shows selectivity over other prostanoid receptors and enzymes. Antagonist activity of AM211 at the DP2 receptor was confirmed by inhibition of PGD 2 -stimulated guanosine 5Ј-O-[␥-thio]triphosphate binding to membranes expressing human DP2. A basophil activation assay and a whole-blood assay of eosinophil shape change were used to demonstrate the ability of AM211 to potently antagonize PGD 2 -stimulated functional responses in relevant human cells and in the context of a physiologically relevant environment. AM211 exhibits good oral bioavailability in rats and dogs and dose-dependently inhibits 13,14-dihydro-15-keto-PGD 2 -induced leukocytosis in a guinea pig pharmacodynamic assay. AM211 demonstrates efficacy in two animal models of allergic inflammation, including an ovalbumin-induced lung inflammation model in guinea pigs and an ovalbumin-induced mouse model of allergic rhinitis. AM211 represents a potent and selective antagonist of DP2 that may be used clinically to evaluate the role of DP2 in T helper 2-driven allergic inflammatory diseases.

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Section: Discussionmentioning

confidence: 99%

Pharmacology of AM211, a Potent and Selective Prostaglandin D₂Receptor Type 2 Antagonist That Is Active in Animal Models of Allergic Inflammation

Bain¹,

Lorrain²,

Stebbins³

et al. 2011

J Pharmacol Exp Ther

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“…Similarly, PGD 2 is chemotactic for murine bone marrow-derived mast cells and this response is ablated by a CRTH2 antagonist [129] . Correspondingly, elevated numbers of CRTH2-positive macrophages and mast cells are present in nasal mucosa of allergic patients [44] .…”

Section: Further Inflammatory Cells Expressing Crth2mentioning

confidence: 99%

“…In humans, sequence variants of the gene encoding CRTH2 are associated with asthma and allergic phenotypes [42] . In addition, recent data suggest that CRTH2 is also expressed on monocytes [43] and macrophages, and mediates their migration induced by PGD 2 and endotoxin [8,44] . Strikingly, PGD 2 levels in bronchoalveolar lavage fluid of patients with chronic obstructive pulmonary disease correlate inversely with lung function [45] .…”

Section: Receptors For Pgdmentioning

confidence: 99%

CRTH2 and D-Type Prostanoid Receptor Antagonists as Novel Therapeutic Agents for Inflammatory Diseases

et al. 2010

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Accumulation of type 2 T helper (Th2) lymphocytes and eosinophils is a hallmark of bronchial asthma and other allergic diseases, and it is believed that these cells play a crucial pathogenic role in allergic inflammation. Thus, Th2 cells and eosinophils are currently considered a major therapeutic target in allergic diseases and asthma. However, drugs that selectively target the accumulation and activation of Th2 cells and eosinophils in tissues are unavailable so far. Prostaglandin (PG)D₂ is a key mediator in various inflammatory diseases including allergy and asthma. It is generated by activated mast cells after allergen exposure and subsequently orchestrates the recruitment of inflammatory cells to the tissue. PGD₂ induces the chemotaxis of Th2 cells, basophils and eosinophils, stimulates cytokine release from these cells and prolongs their survival, and might hence indirectly promote IgE production. PGD₂ mediates its biologic functions via 2 distinct G protein-coupled receptors, D-type prostanoid receptor (DP), and the chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2). DP and CRTH2 receptors are currently being considered as highly promising therapeutic targets for combating allergic diseases and asthma. Here, we revisit the roles of PGD₂ receptors in the regulation of eosinophil and Th2 cell function and the efforts towards developing candidate compounds for clinical evaluation.

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“…It is involved in the chemotaxis of Th2 lymphocytes, eosinophils, mast cells and basophils [16][17][18][19], and inhibits the apoptosis of Th2 lymphocytes [20]. Moreover, CRTh2 activation has a role in the production of IL4, IL5, and IL13 [21] which are cytokines involved in important biological responses like eosinophil recruitment and survival, mucus secretion, airway hyperresponsiveness and immunoglobulin E (IgE) production among others.…”

Section: Introductionmentioning

confidence: 99%

Pharmacological characterization of CRTh2 antagonist LAS191859: Long receptor residence time translates into long-lasting in vivo efficacy

Calbet

Andrés

Armengol

et al. 2016

Pharmacological Research

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Accumulation of CRTH2-positive leukocytes in human allergic nasal mucosa

Cited by 32 publications

References 22 publications

Pharmacology of AM211, a Potent and Selective Prostaglandin D₂Receptor Type 2 Antagonist That Is Active in Animal Models of Allergic Inflammation

Pharmacology of AM211, a Potent and Selective Prostaglandin D₂Receptor Type 2 Antagonist That Is Active in Animal Models of Allergic Inflammation

CRTH2 and D-Type Prostanoid Receptor Antagonists as Novel Therapeutic Agents for Inflammatory Diseases

Pharmacological characterization of CRTh2 antagonist LAS191859: Long receptor residence time translates into long-lasting in vivo efficacy

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Accumulation of CRTH2-positive leukocytes in human allergic nasal mucosa

Cited by 32 publications

References 22 publications

Pharmacology of AM211, a Potent and Selective Prostaglandin D2Receptor Type 2 Antagonist That Is Active in Animal Models of Allergic Inflammation

Pharmacology of AM211, a Potent and Selective Prostaglandin D2Receptor Type 2 Antagonist That Is Active in Animal Models of Allergic Inflammation

CRTH2 and D-Type Prostanoid Receptor Antagonists as Novel Therapeutic Agents for Inflammatory Diseases

Pharmacological characterization of CRTh2 antagonist LAS191859: Long receptor residence time translates into long-lasting in vivo efficacy

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Pharmacology of AM211, a Potent and Selective Prostaglandin D₂Receptor Type 2 Antagonist That Is Active in Animal Models of Allergic Inflammation

Pharmacology of AM211, a Potent and Selective Prostaglandin D₂Receptor Type 2 Antagonist That Is Active in Animal Models of Allergic Inflammation