NDLI: Treatment of Allergic Airway Inflammation and Hyperresponsiveness by Antisense-Induced Local Blockade of Gata-3 Expression

Content Provider	PubMed Central
Author	Finotto, Susetta Sanctis, George T. De Lehr, Hans A. Herz, Udo Michael, Buerke Schipp, Mechthild Bartsch, Brigitte Atreya, Raja Schmitt, Edgar Galle, Peter R. Renz, Harald Neurath, Markus F.
Copyright Year	2001
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 airway 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.
Starting Page	1247
File Format	PDF
ISSN	15409538
e-ISSN	15409538
Journal	The Journal of Experimental Medicine
Issue Number	11
Volume Number	193
Language	English
Publisher	The Rockefeller University Press
Publisher Date	2001-06-04
Access Restriction	Open
Rights Holder	The Rockefeller University Press
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Immunology and Allergy Immunology

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

Treatment of Allergic Airway Inflammation and Hyperresponsiveness by Antisense-Induced Local Blockade of Gata-3 Expression

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