Optimal animal models for human atopic dermatitis (AD), which fully recapitulate key characteristics of AD such as, reduced filaggrin and increased TSLP expression, increased number of epidermal Langerhans, eosinophils, mast cells and a dermal Th2 cytokine profile, ideally in human skin, urgently to be developed, not the least for preclinical R&D. Here we report the development of a novel, humanized mouse model of AD, in which xenotransplanted healthy human skin on SCID mice are i.d injected one month after transplantation with autologous PBMCs that were pre-stimulated in vitro by a combination of the Th2-type cytokine, IL-4, and LPS. Features of AD were observed  within 14 days after the injection. Given that psychoemotional stress triggers flare-ups in many AD patients, we next tested the effect of perceived (sonic) stress, in the new humanized AD mouse model during a dexamethasone-induced remission phase. This showed the reappearance of typical AD lesions in human skin xenotransplants 14 days after exposure to sound stress for 24 hours, thus further documenting that perfectly recapitulates human AD. Finally, we tested the therapeutic response of established human xenotransplant AD lesions to classical and novel AD treatment regimens. A complete normalization of AD lesions in human skin grafts was observed in mice treated i.p with the NK1 antagonist, aprepitant, as well as with topical dexamethasone or tacrolimus compared to vehicle-treated mice, while AD lesions were completely unresponsiveness to oral treatment with the PDE4 inhibitor, apremilast. This contradicts the claimed ineffectiveness of aprepitant in a (likely misleading) murine "AD" model, but is perfectly in line with previously reported therapeutic effects of aprepitant, glucocorticosteroids and tacrolimus in AD patients.Thus, the novel humanized AD mouse model constitutes a major advance in preclinical AD research, and promises to be more predictive for the clinical response seen with candidate AD treatment strategies than any other preclinical AD model.

Development of a novel, perceived stress-sensitive humanized mouse model of atopic dermatitis