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Signal transducer and activator of transcription 1 decoy oligodeoxynucleotide suppression of contact hypersensitivity  Andreas H. Wagner, PhD, Inka Wittjen,

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Presentation on theme: "Signal transducer and activator of transcription 1 decoy oligodeoxynucleotide suppression of contact hypersensitivity  Andreas H. Wagner, PhD, Inka Wittjen,"— Presentation transcript:

1 Signal transducer and activator of transcription 1 decoy oligodeoxynucleotide suppression of contact hypersensitivity  Andreas H. Wagner, PhD, Inka Wittjen, MD, Tomislav Stojanovic, MD, Peter Middel, MD, Josef G. Meingassner, DVM, Markus Hecker, PhD  Journal of Allergy and Clinical Immunology  Volume 121, Issue 1, Pages e5 (January 2008) DOI: /j.jaci Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 Fig 1 Detection of Texas Red–labeled STAT1 dODN penetration into guinea pig skin. A, Time-dependent uptake of the fluorescent dODN (0.2% ointment). B, Detection of the fluorescent dODN in the epidermis (1) and a hair follicle (2) 6 hours after topical application. The right panel shows 4′-6-diamidino-2-phenylindole dihydrochloride (DAPI)–stained nuclei. Scale bar, 100 μm. Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 Fig 2 Topical STAT1 dODN treatment reduces the macroscopic (A) and histopathologic (B) signs of inflammation, as well as the increase in epidermal thickness (C), in the guinea pig CHS model 24 hours after challenge with DNCB. Statistical summary of the evaluation of 18 and 6 (clobetasol) test sites, respectively, is shown. ∗P < .05 versus DNCB plus vehicle; †P < .05 versus 0.13% STAT1 dODN. Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 Fig 3 STAT1 dODN attenuation of neutrophil (A), T-cell (B), and monocyte/macrophage (C) infiltration into the guinea pig skin 24 hours after DNCB challenge. Statistical summary of the mean cell count per unit area in 3 to 5 random fields of view of 18 and 6 (clobetasol) specimens, respectively, is shown. ∗P < .05 versus DNCB plus vehicle; †P < .05 versus 0.13% STAT1 dODN. Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5 Fig 4 STAT1 dODN suppression of DNCB-induced mRNA expression of IL-1β (A), IL-8 (B), IFN-γ (C), IL-12p40 (D), and TNF-α (E) in the guinea pig skin 24 hours after challenge. Statistical summary of real-time PCR data obtained with 18 and 6 (clobetasol) biopsy specimens, respectively, is shown. ∗P < .05 versus DNCB plus vehicle and 0.13% control ODN; †P < .05 versus STAT1 dODN. Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

6 Fig 5 STAT1 dODN–mediated decrease in IL-8 and CD40 protein abundance in guinea pig skin biopsy specimens taken 24 hours after challenge with DNCB. Representative immunohistochemistry analyses are shown. Scale bar, 50 μm (IL-8) and 100 μm (CD40), respectively. Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

7 Fig 6 Topical STAT1 dODN treatment diminishes the clinical signs of CHS in the domestic pig model (A) and edema formation in the mouse model (B). Statistical summary of the scoring of 6 to 12 test sites in the preventive treatment arm 24 hours after DNFB challenge is shown in Fig 6, A. ∗P < .05, ∗∗P < .01, and ∗∗∗P < .001 versus vehicle. Statistical summary of the changes in ear weight (difference in milligrams between challenged and unchallenged ear) in 8 animals each 24 and 48 hours after challenge with FITC is shown in Fig 6, B. ∗P < .05 and ∗∗∗P < .001 versus vehicle. Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

8 Activation of AP-1 and STAT1 in guinea pig skin biopsy specimens collected 24 hours after challenge with DNCB. Appropriate [γ-32P]adenosine triphosphate–labeled gel shift oligonucleotides were used for detection of either transcription factor in nuclear extracts of these specimens (representative EMSA). Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

9 Exemplary results demonstrating the inhibitory effect of the topical STAT1 dODN formulation on the macroscopic (A) and histopathologic (B) signs of inflammation in the guinea pig model of contact hypersensitivity 24 hours after challenge with DNCB. In Fig E2, B, the comparable effect of 0.13% STAT1 dODN ointment and 0.25% clobetasol propionate on epidermal spongiosis and leukocyte infiltration is readily apparent. Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

10 STAT1 dODN–mediated reduction in neutrophil (A), T-cell (B), and monocyte/macrophage (C) infiltration into guinea pig skin 24 hours after DNCB challenge. Representative images are shown. Scale bar, 100 μm. Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

11 Specificity of the STAT dODN in cultured PAECs
Specificity of the STAT dODN in cultured PAECs. IFN-γ (1000 U/mL, 30 minutes)–induced nuclear translocation of STAT1 is significantly reduced in cells pretreated with the consensus (cons) STAT1 dODN (10 μmol/L, 4 hours) but not the corresponding scrambled (scr) control ODN. A sis-inducible element gel shift oligonucleotide was used for detection of STAT1 in the nuclear extracts. Correct assignment of the STAT1-containing DNA-protein complex was confirmed by means of gel shift supershift (SS) analysis with a specific IgG antibody. Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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