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: Clare Murray, Kim Ahrens, Matt Devalaraja, Mike Dymond, Malbinder Fagura, Adam Hargreaves, Alison Holt, Ian Peers, Sally Price, Jaimini Reens, Rob Riley, Rosanna Marsella
• Journal: The Journal of investigative dermatology (J Invest Dermatol) Vol. 136 Issue 3 Pg. 665-671 (Mar 2016) ISSN: 1523-1747 [Electronic] United States
• PMID: 26876716 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Allergens
• Receptors, CCR4

Topics

• Allergens (pharmacology)
• Animals
• Area Under Curve
• Biopsy, Needle
• Cross-Over Studies
• Dermatitis, Atopic (drug therapy, pathology)
• Disease Models, Animal
• Dogs
• Female
• Humans
• Immunohistochemistry
• Male
• Random Allocation
• Receptors, CCR4 (administration & dosage, antagonists & inhibitors)
• Reference Values
• Treatment Outcome