Histamine H₄ receptor antagonist ameliorates chronic allergic contact dermatitis induced by repeated challenge

Background: The present study observed effects of the histamine H ₄ receptor on chronic allergic contact dermatitis induced by repeated challenge in mice. Methods: Acute contact dermatitis was induced by single epicutaneous challenge of 2,4,6-trinitro-1-chlorobenzene (TNCB) to the ear. Chronic allergic contact dermatitis was developed by repeated epicutaneous challenge using TNCB on the dorsal back skin. H₄ receptor antagonist JNJ7777120 was administered to wild-type mice, while H₄ receptor agonist 4-methylhistamine was administered to histidine decarboxylase (HDC) (-/-) mice that synthesized no histamine. Results: HDC (-/-) mice did not differ phenotypically from HDC (+/+) mice, and H₄ receptor antagonist/agonist did not have clinical effects in terms of acute contact dermatitis reactions. H₄ receptor antagonist ameliorated skin eczematous lesions induced by repeated TNCB challenge in HDC (+/+) mice. On the contrary, H₄ receptor agonist exacerbated skin lesions exclusively in HDC (-/-) mice. Application of H₄ receptor agonist induced migration of mast cells and eosinophils in skin lesions, and H₄ receptor antagonist suppressed these changes. H₄ receptor was immunohistochemically detected on mast cells in eczematous lesions. Levels of interleukin (IL)-4, -5, and -6 in lesions were decreased, whereas levels of interferon-γ and IL-12 were increased by H₄ receptor antagonistic activity. Serum Immunoglobulin E levels rapidly increased with repeated challenge, but decreased with H₄ receptor antagonist. Conclusion: Because chronic allergic contact dermatitis is developed by H ₄ receptor stimulation, H₄ receptor antagonists might represent new candidate drugs for treating chronic allergic contact dermatitis.