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.

Molecular Mechanisms of Cutaneous Inflammatory Disorder: Atopic Dermatitis

“…CCL17 promotes the Th2 response via CCR4. The number of CCR4-expressing lymphocytes in serum is correlated with AD severity, the serum IgE level and the blood eosinophil count [180,181]. Furthermore, increased CCL17 levels in cord blood are associated with the development of infantile AD [182].…”

Potential roles of the CCL17‐CCR4 axis in immunopathogenesis of oral lichen planus

“…Previous studies have shown that the CCL17-CCR4 axis is associated with immunologically mediated diseases, such as systemic lupus erythematosus (SLE), atopic dermatitis, and asthma. [11][12][13] In addition, there is evidence to support that CCR4 is a necessary component of skin-specific lymphocyte trafficking. 9,10 Previous studies reported overexpression of CCL17 and CCR4 in OLP tissue.…”

A pilot study on the effect of oclacitinib on epicutaneous sensitization and transepidermal water loss in a colony of atopic beagle dogs

“…Ten atopic beagles previously sensitized epicutaneously to both environmental and food allergens and housed in a controlled allergen environment were used . There had been no prior exposure to Bermuda grass allergen.…”

“…Our primary aim was to investigate if oclacitinib affected epicutaneous sensitization using a placebo‐controlled prospective design. A colony of atopic beagle dogs was used in a controlled environment with standardized allergen exposure . The second aim was to investigate the effect of oclacitinib on skin permeability by measuring transepidermal water loss (TEWL).…”