Tacrolimus ointment causes inflammatory dendritic epidermal cell depletion but no Langerhans cell apoptosis in patients with atopic dermatitis

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Abstract

Background

The topical immunomodulators tacrolimus and pimecrolimus are novel therapeutic options for atopic dermatitis (AD). The inhibition of nuclear factor of activated T cell–dependent proinflammatory cytokine production in cutaneous lymphocytes is an established effect of topical immunomodulators, which additionally influence mast cells, eosinophils, and dendritic cells (DCs). The latter include a reduced expression of the high-affinity IgE receptor FcεRI, a reduced stimulatory capacity of lesional DCs, and a selective depletion of the inflammatory dendritic epidermal cells (IDECs) but not of Langerhans cells (LCs) from the lesional skin.

Objective

Because induction of apoptosis in lymphocytes is a reported tacrolimus effect, we asked whether tacrolimus ointment induces apoptosis of LCs or IDECs in AD lesions.

Methods

Epidermal single-cell suspensions were prepared from AD lesions of 9 tacrolimus-treated and 5 hydrocortisone butyrate–treated patients with AD before and after 1 week of treatment. Cell numbers, apoptosis rate, and immunophenotype were assessed by using the standardized FACS technique with terminal deoxynucleotidyltransferase–mediated dUTP nick end labeling, Annexin V, and 3-color immunophenotyping. Freshly isolated LCs and monocyte-derived DCs served as in vitro controls.

Results

Tacrolimus and steroid ointment induced a selective depletion of IDECs from the epidermis and reduced the expression of the costimulatory molecules CD80 and CD86. Tacrolimus ointment did not increase the rate of apoptotic DCs, whereas steroid ointment did so. The isolation-induced high apoptosis rate of freshly isolated LCs was unaffected by both drugs.

Conclusion

Tacrolimus ointment selectively depletes IDECs and alters the immunophenotype of epidermal DCs in AD lesions, but there is no evidence for tacrolimus-induced DC apoptosis in this phenomenon.

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