The putative lipid raft modulator miltefosine displays immunomodulatory action in T-cell dependent dermal inflammation models

Abstract

Miltefosine is currently marketed for treatment of skin metastasis of breast cancer and leishmaniasis. The mechanism of action is not fully understood, however, miltefosine is considered to be a prototype lipid raft modulator. The compound was shown to inhibit anti-IgE induced histamine release from human skin mast cells. After topical treatment it reduced skin reaction in allergic human volunteers undergoing a skin prick test. The aim of this study was to test whether miltefosine could also modify T-cell signalling and whether the drug may be useful for the treatment of atopic dermatitis. Miltefosine (20 µM) inhibited T-cell proliferation by > 50% in the mixed leukocyte test. In the toluene diisocyanate induced ear swelling test, miltefosine, administered topically as 2 and 6% solution or orally, attenuated ear swelling reaching 70% of the effect of dexamethasone at 100 mg/kg p.o. ( P < 0.01). The ear tissue content of the cytokines IL1ß, IL4 and IL6 was also reduced reaching 56% or 52% reduction of IL1ß ( P < 0.01) after 2% topical or 100 mg/kg p.o. Miltefosine significantly attenuated the allergic sensitization in the model of ovalbumin induced delayed - type hypersensitivity in mice. In a model of toluene diisocyanate induced scratching a significant ( P = 0.0047) reduction of scratching from 47 to 6 bouts was achieved with 100 mg/kg p.o. The data indicate that miltefosine modulates T-cell function in models for Th1 and Th2 related activity. This profile opens up the possibility for the treatment of T-cell related allergic diseases with a novel class of lipid raft modulator drugs such as miltefosine.