Combined treatment with H1 and H4 receptor antagonists reduces inflammation in a mouse model of atopic dermatitis Hanna Köchling a , Katrin Schaper b , Jenny Wilzopolski a , Ralf Gutzmer b , Thomas Werfel b , Wolfgang Bäumer c , Manfred Kietzmann a , Kristine Rossbach a, * a University of Veterinary Medicine Hannover, Institute for Pharmacology, Toxicology and Pharmacy, Hannover, Germany b Hannover Medical School, Division of Immunodermatology and Allergy Research, Department of Dermatology and Allergy, Hannover, Germany c NC State University, College of Veterinary Medicine, Department of Molecular Biomedical Sciences, Raleigh, USA A R T I C L E I N F O Article history: Received 4 November 2016 Received in revised form 5 April 2017 Accepted 12 April 2017 Keywords: Atopic dermatitis Histamine 1 receptor Histamine 4 receptor Inflammation Ovalbumin A B S T R A C T Background: Histamine 4 receptor (H4R) antagonists are considered as new therapeutics for the treatment of atopic dermatitis (AD) and first clinical trials have already shown promising results. Histamine 1 receptor (H1R) antagonists are traditionally used to treat AD although the evidence for the efficacy is weak. The combined blockade of both, H1R and H4R, might provide synergistic anti- inflammatory. Objective: The study was performed to test the anti-inflammatory potential of a combined treatment with an H1R and an H4R antagonist in a mouse AD model. Methods: The development of ovalbumin-induced AD-like skin lesions was analysed mice treated with the H1R inverse agonist mepyramine, the H4R antagonist JNJ-39758979 or a combination of both. Results: Mice treated with mepyramine plus JNJ-39758979 showed less severe skin lesions, with a diminished influx of inflammatory cells, a reduced epidermal thickening and a lower level of IL-33 in lesional skin. Scratching behaviour was ameliorated in mice treated with the combination. Moreover, total numbers of skin-draining lymph node cells and splenocytes were significantly reduced. Both substances given alone did not elicit this strong anti-inflammatory effect. Conclusion: H1R and H4R antagonists provide synergistic anti-inflammatory effects in a mouse model of AD. The combined therapy with H1R and H4R antagonists might represent a new strategy for the treatment of AD. © 2017 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved. 1. Introduction Histamine 1 receptor (H1R) antagonists belong to one of the largest class of medications used in the treatment of allergic diseases [1]. However in case of atopic dermatitis (AD) evidence for the efficacy of H1R-antihistamines is only weak [1]. The histamine 4 receptor (H4R) is considered to be a new therapeutic target for the treatment of AD [2,3]. In a mouse model of AD, clinical signs are clearly attenuated in H4R knockout mice [4]. Moreover, first H4R antagonists have already entered clinical trials in AD patients. The H4R antagonist JNJ-39758979 relieved pruritus and decreased the median Eczema Area and Severity Index (EASI) in patients with moderate AD [5]. In addition, the H4R antagonist ZPL-389 significantly reduced clinical symptoms of moderate to severe AD in a phase 2a proof of concept study from Ziarco Pharma (data published June 2016). In mouse models of hapten-induced allergic dermatitis, the combination of H1R and H4R antagonists showed synergistic inhibition of pruritus [6] and inflammation [7]. The combination was significantly more effective against pruritus than an H1R or an H4R antagonist given alone [6]. In a model of chronic allergic dermatitis (induced by the hapten picryl chloride) established in NC/Nga mice, the anti-inflammatory effect of a combined treatment was similar to that of prednisolone [7]. Thus, the combination of H1R and H4R antihistamines could be a new therapeutic option for chronic allergic skin disease like AD, and might be superior to H4R (and H1R) antagonists given alone. However also the H4R antagonist JNJ-7777120 alone ameliorated picryl chloride skin lesions in NC/Nga mice [7], whereas house dust Abbreviations: AD, atopic dermatitis; EASI, Eczema Area and Severity Index; H1R, histamine 1 receptor; H4R, histamine 4 receptor; OVA, ovalbumin. * Corresponding author at: University of Veterinary Medicine, Foundation, Institute for Pharmacology, Toxicology and Pharmacy, Bünteweg 17, 30559 Hannover, Germany. E-mail address: kristine.rossbach@tiho-hannover.de (K. Rossbach). http://dx.doi.org/10.1016/j.jdermsci.2017.04.004 0923-1811/ © 2017 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved. Journal of Dermatological Science 87 (2017) 130–137 Contents lists available at ScienceDirect Journal of Dermatological Science journal homepa ge: www.jdsjournal.com