Pimecrolimus does not affect the differentiation, maturation and function of human monocyte-derived dendritic cells, in contrast to corticosteroids

Abstract

SUMMARYClinically, corticosteroids (CS) are among the first line drugs in the therapy of autoimmune and allergic diseases and potently inhibit the activation of immune cells. However, due to their pleiotropic mode of action, the prolonged use of CS is generally associated with a range of undesirable side-effects. In this study, we compared the activity of pimecrolimus, a novel immunomodulatory drug for the treatment of inflammatory skin disorders, and the CS dexamethasone (Dex) and beta-methasone-valerate ( b -MSV) in different in vitro assays addressing the cytokine-induced differentiation and maturation of monocytederived dendritic cells (M-DC), the susceptibility of M-DC to drug-induced apoptosis and the potency of differentiated M-DC to induce primary T cell activation. In contrast to pimecrolimus, Dex and b -MSV strongly induced apoptosis of M-DC precursors if added at the start of the DC differentiation culture. Flow cytometric analysis of surviving cells on day 6 of culture showed that the expression of several DC-specific antigens such as CD1a, CD40 and CD80 was inhibited by 50% to 80% at concentrations between 1 n M and 10 n M of either Dex or b -MSV. Furthermore, the presence of CS during the final maturation of M-DC inhibited the synthesis of IL-12p70, the expression of critical DC costimulatory molecules, such as CD83 and CD86 and impaired their ability to activate primary CD4 + T cell proliferation. In contrast, pimecrolimus did not inhibit the LPS-induced secretion of IL-12, surface expression of costimulatory molecules or the maturation of M-DC into potent stimulators of T cells. Taken together, these data indicate that pimecrolimus does not interfere with the differentiation and viability of dendritic cells and their precursors or with the function of mature M-DC to prime naïve T lymphocytes, and thus may have a lower potential than CS to interfere with DC-mediated immunosurveillance.

Effect of Skin Sensitizers on Inducible Nitric Oxide Synthase Expression and Nitric Oxide Production in Skin Dendritic Cells: Role of Different Immunosuppressive Drugs

“…This inhibitory effect of dexamethasone on the iNOS/NO pathway in DC, apart from a known effect on T cells and keratinocytes, may account for some of the antiinflammatory properties of topical corticosteroids observed in inflammatory skin conditions (38)(39)(40)(41)(42) . A more pronounced inhibition of dexamethasone in the process of activation of DC by allergens, both during sensitization and the afferent phase of ACD elicitation, can sustain why medium/potent topical and systemic steroids are more effective in the treatment of ACD than the recently commercialized topical immunosuppressors, tacrolimus and pimecrolimus, which act through molecular mechanisms similar to cyclosporin A and sirolimus.…”

“…Accordingly, recent reports showed that pimecrolimus, a nonsteroid calcineurin inhibitor, has little effect on DC differentiation, maturation and immune function, in contrast to corticosteroids that showed pronounced effects on DC (38)(39)(40)(41) . When compared with calcineurin inhibitors, namely cyclosporin A and tacrolimus, corticosteroids have a unique and profound inhibitory effect on the generation and function of DC (42) .…”

Immunomodulation and Safety of Topical Calcineurin Inhibitors for the Treatment of Atopic Dermatitis

“…More specifically, in an in vitro study of mononuclear cells obtained from healthy volunteers, corticosteroids have been shown to cause apoptosis of monocyte-derived DC (M-DC) precursors and inhibit the expression of DC-specific antigens such as CD1a, CD40, and CD80. In addition, corticosteroids inhibit the expression of critical DC factors such as CD83 and CD86, the synthesis of IL-12p70, and the ability of DCs to activate primary CD4+ T cell proliferation [24]. Topical corticosteroids also have an adverse effect on IL-12 expression in LCs/DCs.…”

“…Topical short-term treatment of even low potency corticosteroids eliminates LCs in the skin by inducing apoptosis. Experimental data show that after stopping application of topical corticosteroids, repopulation of the epidermis with LCs takes weeks [24,25,26,27]. …”

Safety and Tolerability of 1% Pimecrolimus Cream Among Infants: Experience With 1133 Patients Treated for Up to 2 Years

“…19,20 It does not interfere with the differentiation, maturation, and function of cells involved in immunosurveillance, specifically dendritic cells/Langerhans cells. [21][22][23][24][25] Pimecrolimus cream has demonstrated a much lower potential for percutaneous absorption than TCSs, because of its higher molecular weight and lipophilicity. 26,27 Unlike TCSs, it does not cause skin atrophy and does not affect the hypothalamic-pituitary-adrenal axis.…”