Calcipotriol inhibits the proliferation of hyperproliferative CD29 positive keratinocytes in psoriatic epidermis in the absence of an effect on the function and number of antigen-presenting cells

Abstract

The aim of this study was to elucidate some of the possible mechanisms of action of the vitamin D analogue calcipotriol in vivo. Calcipotriol is finding increasing use in the treatment of psoriasis, but the primary target cell in vivo has not yet been identified. We treated psoriatic patients and healthy volunteers with calcipotriol and placebo ointment for 4 and 7 days, and obtained epidermal cell suspensions from treated areas. Epidermal cells were cocultured with autologous T cells, isolated from peripheral blood, in the absence or the presence of a classical antigen or a superantigen. In both psoriatic and normal skin, calcipotriol treatment did not alter the capacity of epidermal antigen-presenting cells to stimulate the proliferation of autologous T cells, either in the absence or in the presence of exogenous antigen. Epidermal cell suspensions were analysed further by staining for infiltrating leucocytes (CD45+) and Langerhans cells (CD1a+). Flow cytometric analysis showed that calcipotriol did not alter the number of CD45+ cells or Langerhans cells in psoriatic skin. These results indicate that calcipotriol does not alter either the number of the function of epidermal antigen-presenting cells in psoriatic epidermis. In contrast, we found that calcipotriol significantly inhibited the proliferation of epidermal cells isolated from psoriatic skin after in vivo treatment, as determined by propidium iodide staining and flow cytometry. More specifically, we stained for CD29+ keratinocytes and found an even more significant reduction in proliferative capacity. This cell type contains the population of hyperproliferative keratinocytes in psoriatic epidermis. In conclusion, calcipotriol seems to act via an inhibitory effect on hyperproliferative basal keratinocytes of psoriatic epidermis, rather than via an effect on infiltrating leucocytes, including antigen-presenting cells.

Mechanisms of action of topical therapies and the rationale for combination therapy

“…14,15 Erythema often persists after scale clearing and reduction in plaque thickness following treatment with the agent, 15 which does not appear to alter the function or number of antigenpresenting cells in psoriatic lesions. 16 Of note, the use of calcipotriene cream with other topical agents at acidic pH may result in the inactivation of calcipotriene; therefore topical calcipotriene preparations should not be used simultaneously with agents such as salicylic acid or lactic acid. 19 …”

“…15,16 These actions are probably mediated via binding with vitamin Deselective receptors located in the nucleus of epidermal keratinocytes. 14 Vitamin D receptors are also found in dermal fibroblasts, T and B lymphocytes, monocytes, and macrophages; activation of these receptors also may play a role in the antipsoriatic effects of calcipotriene.…”

Calcipotriol plus betamethasone dipropionate gel in the treatment of scalp psoriasis

“…Eine Inhibition der Keratinozytenproliferation und die Induktion der Zelldifferenzierung stellen die zentrale Wirkung der Vitamin-D 3 -Analoga dar [20,24,32]. Daneben zeigen sich auch immunmodulatorische Effekte auf T-Lymphozyten, Langerhans-Zellen und Monozyten, während bei den topischen Glukokortikoiden ein rein antientzünd-licher Effekt im Vordergrund steht [25,45] So fand man weiterhin als Folge der Einwirkung von Vitamin-D-Metaboliten auf kultivierte Keratinozyten u. a. eine Supprimierung der DNA-Synthese sowie eine verstärkte Bildung von terminal ausdifferenzierten Zellen, erkenntlich an den "cornified envelopes" (Hornzellmäntel).…”

A clinician's paradigm in the treatment of psoriasis

“…This agent binds with vitamin De selective receptors in various cell types important in the pathogenesis of psoriasis and has been shown to inhibit the hyperproliferation and abnormal differentiation of keratinocytes characteristic of psoriatic lesions. [7][8][9] Because of the relatively slow onset of action of calcipotriene, other agents, such as corticosteroids, may be combined with calcipotriene during the initial weeks of therapy. 10 …”