Treatment of murine atopic dermatitis with a CCL11 antibody and a topical CCR3 inhibitor

Summary: We reported previously that Ikkb deletion in Prx1+ fibroblasts blocks NF-kB activation and surprisingly promotes myelocytic and leukocytic dysregulation in the skin, mimicking atopic dermatitis characterized by eosinophilia and a type II immune response. In this model, skin lesions were associated with dermal and subcutaneous inflammation associated with fibrosis and alopecia. Experiments showed that upregulation of CCL11 and CCR3 drove the inflammatory phenotype. This study aims to determine whether blocking CCR3 and CCL11 signaling with a topical CCR3 inhibitor and systemic CCL11 antibody can induce regression of the spontaneous atopic dermatitis (AD)- like skin lesions in this model. We analyzed Prx1Cre+Ikkbf/f mice that had developed atopic dermatitis-like lesions at 9-10 weeks of age and were subjected them to a combination of a topical CCR3 inhibitor and a systemic CCL11 antibody for 10 weeks. Control mice received vehicles only. Rat anti-mouse CCL11 antibody (approximately 1.0 ug/ul) was administered twice weekly via subcutaneous injection into inflamed lesions with the animal under anesthesia. The CCR3 inhibitor GW766944 was applied topically in a gel daily to the inflamed lesions at a concentration of 25 mM for 10 weeks. Administration of the topical CCR3 inhibitor and systemic CCL11 antibody induced regression of lesional area by approximately 70% compared to controls (P<0.05). Our initial results indicate that blocking the CCR3 with a topical small molecule inhibitor combined with a systemic CCL11 antibody inhibited the formation of atopic dermatitis-like lesions in Prx1Cre+Ikkbf/f mice. These findings indicate that inhibition of CCL11 and CCR3 signaling may be useful for inhibiting maintenance of skin lesions and Th2 inflammation in this murine model of AD. Sara Aldosary², Xianhong Yang², Xiaoping Yang¹, Justin Suh¹, Steve Prouty¹, Dana Graves², John T. Seykora¹ 1. Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States. 2. Department of Periodontics, University of Pennsylvania School of Dental Medicine, Philadelphia, PA, United States. Translational Studies: Preclinical