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.