Topical tacrolimus (FK506) leads to profound phenotypic and functional alterations of epidermal antigen-presenting dendritic cells in atopic dermatitis

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease in which antigen-presenting epidermal dendritic cells (DCs), ie, Langerhans cells and the so-called inflammatory dendritic epidermal cells (IDECs) expressing the high-affinity receptor for IgE (Fc epsilon RI) may play a significant pathophysiologic role. Therapeutic efficacy of the immunosuppressive macrolide tacrolimus (FK506) in AD has been demonstrated in clinical trials, but little is known of its mode of action. Objective: The present study focused on the effects of topical tacrolimus treatment on epidermal CD1a(+)/Fc epsilon RI(+) DC populations in lesional AD. Methods: Immunohistological analysis, epidermal DC phenotyping, and functional studies were performed on skin biopsy specimens from treated and untreated lesional skin of 10 patients with AD participating in a clinical trial with tacrolimus. Results: Untreated lesional skin was characterized by a high proportion of CD1a(+) cells, which was largely due to a high proportion of IDECs strongly expressing Fc epsilon RI. Epidermal DCs isolated from untreated lesional skin exhibited high stimulatory activity toward autologous T cells, which was strongly reduced while clinical improvement was seen during application of tacrolimus. Concomitantly, a decreased Fc epsilon RI expression was observed in both Langerhans cells and IDECs. Finally, topical tacrolimus led to a progressive decrease in the IDEC population within the pool of CD1a(+) epidermal DCs and also to a decrease in their CD36 expression, which is indicative of lower local inflammation. Conclusion: Epidermal CD1a(+) DCs may represent a target for topical tacrolimus in the treatment of AD.