Treatment of allergic airway inflammation and hyperresponsiveness by antisense-induced local blockade of GATA-3 expression

Details

Serval ID
serval:BIB_9BC0C22DA66D
Type
Article: article from journal or magazin.
Collection
Publications
Title
Treatment of allergic airway inflammation and hyperresponsiveness by antisense-induced local blockade of GATA-3 expression
Journal
Journal of Experimental Medicine
Author(s)
Lehr HA, Finotto S, DeSantis GT, Herz U, Buerke M, Schnipp M, Bartsch B, Atreya R, Schmitt E, Galle PR, Renz H, Neurath MF
ISSN
0022-1007
Publication state
Published
Issued date
2001
Peer-reviewed
Oui
Volume
193
Number
11
Pages
1247-1260
Language
english
Abstract
Recent studies in transgenic mice have revealed that expression of a dominant negative form of the transcription factor GATA-3 in T cells can prevent T helper cell type 2 (Th2)-mediated allergic airway inflammation in mice. However, it remains unclear whether GATA-3 plays a role in the effector phase of allergic airway inflammation and whether antagonizing the expression and/or function of GATA-3 can be used for the therapy of allergic airway inflammation and hyperresponsiveness. Here, we analyzed the effects of locally antagonizing GATA-3 function in a murine model of asthma. We could suppress GATA-3 expression in interleukin (IL)-4-producing T cells in vitro and in vivo by an antisense phosphorothioate oligonucleotide overlapping the translation start site of GATA-3, whereas nonsense control oligonucleotides were virtually inactive. In a murine model of asthma associated with allergic pulmonary inflammation and hyperresponsiveness in ovalbumin (OVA)-sensitized mice, local intranasal administration of fluorescein isothiocyanate-labeled GATA-3 antisense oligonucleotides led to DNA uptake in lung cells associated with a reduction of intracellular GATA-3 expression. Such intrapulmonary blockade of GATA-3 expression caused an abrogation of signs of lung inflammation including infiltration of eosinophils and Th2 cytokine production. Furthermore, treatment with antisense but not nonsense oligonucleotides induced a significant reduction of airway hyperresponsiveness in OVA-sensitized mice to levels comparable to saline-treated control mice, as assessed by both enhanced pause (PenH) responses and pulmonary resistance determined by body plethysmography. These data indicate a critical role for GATA-3 in the effector phase of a murine asthma model and suggest that local delivery of GATA-3 antisense oligonucleotides may be a novel approach for the treatment of air-way hyperresponsiveness such as in asthma. This approach has the potential advantage of suppressing the expression of various proinflammatory Th2 cytokines simultaneously rather than suppressing the activity of a single cytokine.
Keywords
GATA-3 antisense DNA, asthma, T cells, Th2 cytokines, TRANSCRIPTION FACTOR GATA-3, CHRONIC INTESTINAL INFLAMMATION, DEVELOPING TH1 CELLS, CD4(+) T-CELLS, MOUSE MODEL, TH2-SPECIFIC EXPRESSION, GENE-EXPRESSION, TRANSGENIC MICE, ATOPIC ASTHMA, MURINE MODEL
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Create date
15/12/2011 21:02
Last modification date
20/08/2019 15:02
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