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

Recent studies in transgenic mice have revealed that expression of a domina nt 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. H owever, it remains unclear whether GATA-3 plays a role in the effector phas e of allergic airway inflammation and whether antagonizing the expression a nd/or function of GATA-3 can be used for the therapy of allergic airway inf lammation and hyperresponsiveness. Here, we analyzed the effects of locally antagonizing GATA-3 function in a murine model of asthma. We could suppres s GATA-3 expression in interleukin (IL)-4-producing T cells in vitro and in vivo by an antisense phosphorothioate oligonucleotide overlapping the tran slation start site of GATA-3, whereas nonsense control oligonucleotides wer e virtually inactive. In a murine model of asthma associated with allergic pulmonary inflammation and hyperresponsiveness in ovalbumin (OVA)-sensitize d mice, local intranasal administration of fluorescein isothiocyanate-label ed GATA-3 antisense oligonucleotides led to DNA uptake in lung cells associ ated with a reduction of intracellular GATA-3 expression. Such intrapulmona ry blockade of GATA-3 expression caused an abrogation of signs of lung infl ammation including infiltration of eosinophils and Th2 cytokine production. Furthermore, treatment with antisense but not nonsense oligonucleotides in duced a significant reduction of airway hyperresponsiveness in OVA-sensitiz ed mice to levels comparable to saline-treated control mice, as assessed by both enhanced pause (PenH) responses and pulmonary resistance determined b y body plethysmography. These data indicate a critical role for GATA-3 in t he effector phase of a murine asthma model and suggest that local delivery of GATA-3 antisense oligonucleotides may be a novel approach for the treatm ent of air-way hyperresponsiveness such as in asthma. This approach has the potential advantage of suppressing the expression of various proinflammato ry Th2 cytokines simultaneously rather than suppressing the activity of a s ingle cytokine.