title: Treatment of allergic airway inflammation and hyperresponsiveness by antisense-induced local blockade of GATA-3 expression.
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.
authors.affiliation: Laboratory of Immunology, University of Mainz, 55099 Mainz, Germany. sfinotto@rics.bwh.harvard.edu
authors.forename: S
authors.initials: S
authors.lastname: Finotto
authors.forename: G T
authors.initials: GT
authors.lastname: De Sanctis
authors.forename: H A
authors.initials: HA
authors.lastname: Lehr
authors.forename: U
authors.initials: U
authors.lastname: Herz
authors.forename: M
authors.initials: M
authors.lastname: Buerke
authors.forename: M
authors.initials: M
authors.lastname: Schipp
authors.forename: B
authors.initials: B
authors.lastname: Bartsch
authors.forename: R
authors.initials: R
authors.lastname: Atreya
authors.forename: E
authors.initials: E
authors.lastname: Schmitt
authors.forename: P R
authors.initials: PR
authors.lastname: Galle
authors.forename: H
authors.initials: H
authors.lastname: Renz
authors.forename: M F
authors.initials: MF
authors.lastname: Neurath
mesh_terms: D000818:Animals; D001249:Asthma / Q000188:drug therapy*; D016535:Bronchial Hyperreactivity / Q000188:drug therapy*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D004804:Eosinophils / Q000502:physiology; D005260:Female; D050990:GATA3 Transcription Factor; D015847:Interleukin-4 / Q000096:biosynthesis; D016906:Interleukin-9 / Q000096:biosynthesis; D008168:Lung / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D010047:Ovalbumin / Q000276:immunology; D018418:Th2 Cells / Q000378:metabolism; D015534:Trans-Activators / Q000037:antagonists & inhibitors*
chemical_list: D004268:DNA-Binding Proteins; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D016906:Interleukin-9; D016376:Oligonucleotides, Antisense; D015534:Trans-Activators; D015847:Interleukin-4; D010047:Ovalbumin