title: Use of a Canine Model of Atopic Dermatitis to Investigate the Efficacy of a CCR4 Antagonist in Allergen-Induced Skin Inflammation in a Randomized Study.
abstract: Atopic dermatitis (AD) is an inflammatory skin disease characterized by infiltration of skin homing lymphocytes into the dermis. Most of these lymphocytes express the chemokine receptor CCR4, and the frequency of blood CCR4(+) lymphocytes correlates with AD disease severity. Canine AD is a pruritic inflammatory condition that shows many features of the human disease, including CCR4 overexpression. Therefore, we tested a potent selective CCR4 antagonist in an allergen challenge model of canine AD, both clinically and histologically, to investigate whether this chemokine pathway plays a role in the inflammatory response. Using a four-period randomized cross-over study design, 14 beagles were challenged with allergen and clinically monitored. Biopsy samples were taken before and after allergen challenge. A clear reduction of clinical scores was observed with oral prednisolone (P < 0.0001) but not for the CCR4 inhibitor. A subset of the dogs (5/13) showed partial inhibition (30-49%) of the clinical signs with CCR4 inhibitor treatment, and this finding was supported by the results of histopathologic analysis of skin biopsy samples. This partial response is consistent with redundancy in chemokine pathways and highlights the need for therapies blocking multiple pathways. This study shows the utility of this canine model of AD for testing new therapeutic agents.
authors.affiliation: AstraZeneca R&D Alderley Park, Macclesfield, Cheshire, UK.
authors.forename: Clare
authors.initials: C
authors.lastname: Murray
authors.affiliation: Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, Florida, USA.
authors.forename: Kim
authors.initials: K
authors.lastname: Ahrens
authors.affiliation: AstraZeneca R&D Boston, Waltham, Massachusetts, USA.
authors.forename: Matt
authors.initials: M
authors.lastname: Devalaraja
authors.affiliation: AstraZeneca R&D Alderley Park, Macclesfield, Cheshire, UK.
authors.forename: Mike
authors.initials: M
authors.lastname: Dymond
authors.affiliation: AstraZeneca R&D Alderley Park, Macclesfield, Cheshire, UK.
authors.forename: Malbinder
authors.initials: M
authors.lastname: Fagura
authors.affiliation: AstraZeneca R&D Alderley Park, Macclesfield, Cheshire, UK.
authors.forename: Adam
authors.initials: A
authors.lastname: Hargreaves
authors.affiliation: AstraZeneca R&D Alderley Park, Macclesfield, Cheshire, UK.
authors.forename: Alison
authors.initials: A
authors.lastname: Holt
authors.affiliation: AstraZeneca R&D Alderley Park, Macclesfield, Cheshire, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Peers
authors.affiliation: AstraZeneca R&D Alderley Park, Macclesfield, Cheshire, UK.
authors.forename: Sally
authors.initials: S
authors.lastname: Price
authors.affiliation: AstraZeneca R&D Alderley Park, Macclesfield, Cheshire, UK.
authors.forename: Jaimini
authors.initials: J
authors.lastname: Reens
authors.affiliation: AstraZeneca R&D Alderley Park, Macclesfield, Cheshire, UK.
authors.forename: Rob
authors.initials: R
authors.lastname: Riley
authors.affiliation: Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, Florida, USA. Electronic address: marsella@ufl.edu.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Marsella
mesh_terms: D000485:Allergens / Q000494:pharmacology; D000818:Animals; D019540:Area Under Curve; D001707:Biopsy, Needle; D018592:Cross-Over Studies; D003876:Dermatitis, Atopic / Q000188:drug therapy* / Q000473:pathology*; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D011897:Random Allocation; D054398:Receptors, CCR4 / Q000008:administration & dosage* / Q000037:antagonists & inhibitors*; D012016:Reference Values; D016896:Treatment Outcome
chemical_list: D000485:Allergens; D054398:Receptors, CCR4