Signal transducer and activator of transcription 1 decoy oligodeoxynucleotide suppression of contact hypersensitivity

• Published in: Journal of allergy and clinical immunology 2008, Vol.121 (1), p.158-165.e5
• Main Authors: Wagner, Andreas H., PhD, Wittjen, Inka, MD, Stojanovic, Tomislav, MD, Middel, Peter, MD, Meingassner, Josef G., DVM, Hecker, Markus, PhD
• Format: Article
• Language: English
• Subjects: allergic contact dermatitis; Allergy and Immunology; Animals; Aorta - cytology; Binding sites; Biological and medical sciences; Cells, Cultured; Chemokines; Contact hypersensitivity; Cytokines; Cytokines - metabolism; decoy oligodeoxynucleotide; Dermatitis; Dermatitis, Contact - drug therapy; Dermatitis, Contact - etiology; Dermatitis, Contact - immunology; Disease; Disease Models, Animal; Drug dosages; Endothelium, Vascular - cytology; Female; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gene expression; Genetic engineering; Guinea Pigs; Hypersensitivity, Delayed - drug therapy; Hypersensitivity, Delayed - etiology; Hypersensitivity, Delayed - immunology; Immunopathology; Inflammation - drug therapy; Inflammation - immunology; Male; Medical sciences; Mice; Mice, Inbred BALB C; Ointments - administration & dosage; Ointments - pharmacokinetics; Ointments - therapeutic use; Oligodeoxyribonucleotides - administration & dosage; Oligodeoxyribonucleotides - genetics; Oligodeoxyribonucleotides - pharmacokinetics; Oligodeoxyribonucleotides - therapeutic use; Olive oil; Psoriasis; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; signal transducer and activator of transcription 1; Skin; Skin - immunology; Skin - pathology; Skin diseases; STAT1 Transcription Factor - antagonists & inhibitors; STAT1 Transcription Factor - genetics; Swine; Transcription factors; Treatment Outcome
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2007.09.015

Background Cytokines play a pivotal role in allergy development through activating signaling mechanisms, such as the Janus kinase/signal transducer and activator of transcription (STAT) pathway, which controls the expression of numerous proinflammatory genes. Objective In comparison with 2 different corticosteroids and a calcineurin inhibitor, the efficacy of a STAT1 decoy oligodeoxynucleotide (dODN)–containing ointment on hapten-induced contact hypersensitivity was examined in 3 different animal models. Methods After sensitization, the test compounds were administered before hapten challenge, after hapten challenge, or both to different sites of the animal skin. Subsequent erythema and edema formation was scored macroscopically, microscopically, or by a shift in ear weight. Biopsy specimens were taken and processed for histopathology, immunohistochemistry, and real-time PCR analyses. Results Treatment with the STAT1 dODN but not the corresponding control ODN markedly improved the clinical signs of inflammation in all 3 animal models in a dose-related manner. In guinea pig skin this was accompanied by a distinct decrease in leukocyte infiltration into the dermis after 24 hours. In addition, expression of CD40, IFN-γ, IL-1β, IL-8, IL-12, and TNF-α was strongly attenuated. The dODN was equally effective in the domestic pig model when administered therapeutically, and its preventive effect in the mouse model lasted for more than 48 hours. Conclusions Altogether, treatment with the dODN proved to be at least as effective as treatment with the reference compounds.