Pimecrolimus Inhibits the Elicitation Phase but Does Not Suppress the Sensitization Phase in Murine Contact Hypersensitivity, in Contrast to Tacrolimus and Cyclosporine A11Results reported in part at the SID meeting 2000 in Chicago (Meingassner J, Fahnrgruber H, Bavandi A: SDZ ASM 981, in contrast to CyA and FK 509, does not suppress the primary immune response in murine allergic contact dermatitis. J Invest Dermatol 114:832, 2000).

Abstract

Pimecrolimus (SDZ ASM 981, Elidel) is a nonsteroid inflammatory cytokine inhibitor specifically developed for the treatment of inflammatory skin diseases. Its effect on the elicitation and sensitization phases of oxazolone-induced contact hypersensitivity was compared with tacrolimus and cyclosporine A (CyA) in BALB/c mice using the ear swelling assay. The compounds were administered orally. Elicitation was dose-dependently inhibited by all three compounds. The minimal effective doses were 30 mg per kg (pimecrolimus, tacrolimus) and 90 mg per kg (CyA), respectively. There was no impairment of sensitization by pimecrolimus up to the highest dose tested (120 mg per kg), in contrast to CyA (60% inhibition at 60 mg per kg) and tacrolimus (71% inhibition at 30 mg per kg). Weight and cellularity of the draining lymph nodes in mice treated with tacrolimus or CyA during sensitization were reduced. In addition, proliferation of T cells after secondary stimulation was inhibited in cell cultures from lymph nodes of mice treated with tacrolimus or CyA. Thus, in contrast to tacrolimus and CyA, pimecrolimus exerts a more selective immunomodulatory effect. It does not impair the primary immune response (sensitization phase) but effectively inhibits the secondary phase, the elicitation phase that is the clinical manifestation of contact hypersensitivity.

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

“…Interestingly, in these experiments, the draining lymph nodes were not affected regarding primary immune response, weight, number, and functionality of lymph node cells, as was seen with tacrolimus [74]. …”

Discovery of Topical Calcineurin Inhibitors and Pharmacological Profile of Pimecrolimus

“…In contrast to CyA and tacrolimus (fig. 8b), oral treatment of mice with pimecrolimus neither impairs the sensitization phase of ACD nor decreases the weight and cellularity of draining lymph nodes, indicating that the primary immune response in ACD is not impaired by pimecrolimus [74]. In rats, oral pimecrolimus is superior to CyA by a factor of 4 and to tacrolimus by a factor of more than 2 in inhibiting the elicitation phase of ACD [72].…”

“…Data represent means ± SEM. Adapted from Meingassner et al [74 ]with permission from Macmillan Publishers. …”

Differential Inhibition of Primary versus Preactivated T Cells by Pimecrolimus but Not by Tacrolimus in vitro

“…Interestingly, pimecrolimus and tacrolimus were shown to have a different pharmacologic profile in a mouse model of allergic contact dermatitis, a delayed-type cutaneous hypersensitivity (CHS) reaction. Whereas pimecrolimus and tacrolimus were equipotent in inhibiting the inflammatory response when administered orally at challenge, pimecrolimus in contrast to tacrolimus did not inhibit the sensitization towards the contact allergen, even at a 4-fold higher dose [11]. The present study shows that pimecrolimus has a more selective activity profile against primed T cells in vitroas compared with tacrolimus.…”

“…The recent observation of a differential profile of systemically applied pimecrolimus and tacrolimus in CHS [11] and the paucity of published data on a side-by-side comparison of the two drugs in vitro led us to investigate their potency in the context of primary and secondary T cell stimulations. Here, we show that pimecrolimus was consistently less active than tacrolimus on freshly isolated PBMC, purified CD4+ T cells or pan T cells containing both CD4+ plus CD8+ T cell subsets.…”