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.
复制标题
通过反义诱导的GATA-3表达的局部阻断来治疗过敏性气道炎症和反应性过高。
DOI：
10.1084/jem.193.11.1247
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发表时间：
2001-06-04
影响因子：
15.3
通讯作者：
Neurath, M F
中科院分区：
文献类型：
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作者：
Finotto, S;De Sanctis, G T;Lehr, H A;Herz, U;Buerke, M;Schipp, M;Bartsch, B;Atreya, R;Schmitt, E;Galle, P R;Renz, H;Neurath, M F
最近在转基因小鼠中的研究已经揭示，T细胞中转录因子加塔-3的显性负性形式的表达可以预防小鼠中T辅助细胞2型（Th 2）介导的过敏性气道炎症。然而，加塔-3是否在变应性气道炎症的效应期起作用以及拮抗加塔-3的表达和/或功能是否可用于治疗变应性气道炎症和高反应性仍不清楚。在这里，我们分析了局部拮抗加塔-3功能在小鼠哮喘模型中的作用。我们可以抑制加塔-3表达白细胞介素（IL）-4-生产T细胞在体外和体内的反义硫代磷酸寡核苷酸重叠的翻译起始位点的加塔-3，而无义对照寡核苷酸几乎是无活性的。在卵清蛋白（OVA）致敏小鼠中，局部鼻内给予异硫氰酸荧光素标记的加塔-3反义寡核苷酸导致肺细胞中DNA摄取，与细胞内加塔-3表达减少相关。这种肺内阻断加塔-3表达导致肺部炎症体征的消除，包括嗜酸性粒细胞浸润和Th 2细胞因子产生。此外，治疗与反义寡核苷酸，而不是无义寡核苷酸诱导的OVA致敏小鼠的气道高反应性显着降低到与盐水治疗的对照组小鼠的水平，评估增强暂停（PenH）的反应和肺阻力确定的身体体积描记法。这些数据表明加塔-3在小鼠哮喘模型的效应期中的关键作用，并表明局部递送加塔-3反义寡核苷酸可能是治疗气道高反应性（例如哮喘）的新方法。这种方法具有同时抑制各种促炎性Th 2细胞因子的表达而不是抑制单一细胞因子的活性的潜在优势。
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.