title: 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 (20microM) 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 100mg/kg p.o. (P<0.01). The ear tissue content of the cytokines IL1beta, IL4 and IL6 was also reduced reaching 56% or 52% reduction of IL1beta (P<0.01) after 2% topical or 100mg/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 100mg/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.
authors.affiliation: Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Hannover, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Bäumer
authors.forename: Piotr
authors.initials: P
authors.lastname: Wlaź
authors.forename: Gary
authors.initials: G
authors.lastname: Jennings
authors.forename: Chris
authors.initials: C
authors.lastname: Rundfeldt
mesh_terms: D000284:Administration, Oral; D000287:Administration, Topical; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use; D016718:Arachidonic Acid / Q000494:pharmacology; D004195:Disease Models, Animal; D004423:Ear / Q000473:pathology; D005260:Female; D006967:Hypersensitivity / Q000276:immunology; D007155:Immunologic Factors / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D021962:Membrane Microdomains / Q000187:drug effects*; D051379:Mice; D010767:Phosphorylcholine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use; D011537:Pruritus / Q000188:drug therapy / Q000276:immunology; D012867:Skin / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D013601:T-Lymphocytes / Q000276:immunology*; D014051:Toluene 2,4-Diisocyanate / Q000276:immunology
chemical_list: D000893:Anti-Inflammatory Agents; D007155:Immunologic Factors; D007378:Interleukins; D010767:Phosphorylcholine; D014051:Toluene 2,4-Diisocyanate; D016718:Arachidonic Acid; C039128:miltefosine