title: Inhibition of the IL-2-inducible tyrosine kinase (Itk) activity: a new concept for the therapy of inflammatory skin diseases.
abstract: T-cell-mediated processes play an essential role in the pathogenesis of several inflammatory skin diseases such as atopic dermatitis, allergic contact dermatitis and psoriasis. The aim of this study was to investigate the role of the IL-2-inducible tyrosine kinase (Itk), an enzyme acting downstream of the T-cell receptor (TCR), in T-cell-dependent skin inflammation using three approaches. Itk knockout mice display significantly reduced inflammatory symptoms in mouse models of acute and subacute contact hypersensitivity (CHS) reactions. Systemic administration of a novel small molecule Itk inhibitor, Compound 44, created by chemical optimization of an initial high-throughput screening hit, inhibited Itk's activity with an IC50 in the nanomolar range. Compound 44 substantially reduced proinflammatory immune responses in vitro and in vivo after systemic administration in two acute CHS models. In addition, our data reveal that human Itk, comparable to its murine homologue, is expressed mainly in T cells and is increased in lesional skin from patients with atopic dermatitis and allergic contact dermatitis. Finally, silencing of Itk by RNA interference in primary human T cells efficiently blocks TCR-induced lymphokine secretion. In conclusion, Itk represents an interesting new target for the therapy of T-cell-mediated inflammatory skin diseases.
authors.affiliation: Corporate Development-Innovation, Bayer AG, Leverkusen, Germany. arnevon.bonin@bayer.com
authors.forename: Arne
authors.initials: A
authors.lastname: von Bonin
authors.forename: Alexandra
authors.initials: A
authors.lastname: Rausch
authors.forename: Anne
authors.initials: A
authors.lastname: Mengel
authors.forename: Marion
authors.initials: M
authors.lastname: Hitchcock
authors.forename: Martin
authors.initials: M
authors.lastname: Krüger
authors.forename: Oliver
authors.initials: O
authors.lastname: von Ahsen
authors.forename: Claudia
authors.initials: C
authors.lastname: Merz
authors.forename: Lars
authors.initials: L
authors.lastname: Röse
authors.forename: Christine
authors.initials: C
authors.lastname: Stock
authors.forename: Stefan F
authors.initials: SF
authors.lastname: Martin
authors.forename: Gabriele
authors.initials: G
authors.lastname: Leder
authors.forename: Wolf-Dietrich
authors.initials: WD
authors.lastname: Döcke
authors.forename: Khusru
authors.initials: K
authors.lastname: Asadullah
authors.forename: Ulrich
authors.initials: U
authors.lastname: Zügel
mesh_terms: D000818:Animals; D001483:Base Sequence; D003872:Dermatitis / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology; D017449:Dermatitis, Allergic Contact / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology; D003876:Dermatitis, Atopic / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology; D004137:Dinitrochlorobenzene / Q000276:immunology / Q000633:toxicity; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D066298:In Vitro Techniques; D008221:Lymphoid Tissue / Q000201:enzymology / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics; D011565:Psoriasis / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D015854:Up-Regulation
chemical_list: D004137:Dinitrochlorobenzene; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase