Signal transducer and activator of transcription 1 decoy oligodeoxynucleotide suppression of contact hypersensitivity.
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-gamma, IL-1beta, IL-8, IL-12, and TNF-alpha 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.
Wagner
Andreas H
AH
Institute of Physiology and Pathophysiology, University of Heidelberg, Heidelberg, Germany.
Wittjen
Inka
I
Stojanovic
Tomislav
T
Middel
Peter
P
Meingassner
Josef G
JG
Hecker
Markus
M
D000818:Animals; D001011:Aorta / Q000166:cytology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003877:Dermatitis, Contact / Q000188:drug therapy* / Q000209:etiology / Q000276:immunology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000166:cytology; D005260:Female; D006168:Guinea Pigs; D006968:Hypersensitivity, Delayed / Q000188:drug therapy / Q000209:etiology / Q000276:immunology; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009824:Ointments / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000235:genetics / Q000493:pharmacokinetics / Q000627:therapeutic use*; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics; D012867:Skin / Q000276:immunology / Q000473:pathology; D013552:Swine; D016896:Treatment Outcome
D016207:Cytokines; D009824:Ointments; D009838:Oligodeoxyribonucleotides; D050794:STAT1 Transcription Factor