Ferrara Tanna J, Mueller Cynthia, Sahu Nisebita, Ben-Jebria Abdellaziz, August Avery
Physiology Graduate Program and Department of Chemical Engineering, Pennsylvania State University, University Park 16802, USA.
J Allergy Clin Immunol. 2006 Apr;117(4):780-6. doi: 10.1016/j.jaci.2005.12.1330. Epub 2006 Feb 7.
Patients with allergic asthma have symptoms of a predominant T(H)2 response, including airway eosinophilic inflammation and increased mucous production in the lungs. This accompanies increased airways responsiveness, which can be life threatening. Because T(H)2 cells and cytokines have been implicated in contributing to these symptoms, pathways that control the development of these cells or that regulate their cytokine production represent good targets for controlling this disease.
We have previously shown that mice lacking the tyrosine kinase inducible T-cell kinase (ITK) have drastically reduced airway inflammation in a model of allergic asthma. However, it was not clear whether this translated into reduced airways hyperresponsiveness. We have analyzed tracheal responsiveness and airways hyperresponsiveness of wild-type (WT) and ITK null mice during induction of experimental allergic asthma.
Experimental allergic asthma was induced in WT and ITK knockout mice. Tracheal responses to carbachol, acetylcholine, and potassium chloride were analyzed. Airways hyperresponsiveness to methacholine challenge was also analyzed in allergen-challenged mice, along with lung and bronchoalveolar lavage fluid T(H)2 cytokine message and protein.
ITK null mice have reduced tracheal responses to cholinergic challenge in vitro before as well as after allergen challenge. These mice also have reduced airways hyperresponsiveness in response to allergen challenge, which could be rescued by transferring WT splenocytes or purified WT CD4+ T cells. This reduced airways response was preferentially accompanied by reduced expression of T(H)2 cytokines in the lungs.
Our results indicate that the tyrosine kinase ITK and its function in T cells represent an attractive target for antiasthmatic drugs.
Modulating the expression or activity of ITK may be a novel strategy to block allergic airway inflammation.
过敏性哮喘患者具有以T(H)2反应为主导的症状，包括气道嗜酸性粒细胞炎症和肺部黏液分泌增加。这伴随着气道反应性增加，可能危及生命。由于T(H)2细胞和细胞因子与这些症状的产生有关，控制这些细胞发育或调节其细胞因子产生的途径是控制该疾病的良好靶点。
我们之前已经表明，在过敏性哮喘模型中，缺乏酪氨酸激酶诱导型T细胞激酶（ITK）的小鼠气道炎症显著减轻。然而，尚不清楚这是否转化为气道高反应性降低。我们分析了野生型（WT）和ITK基因敲除小鼠在实验性过敏性哮喘诱导过程中的气管反应性和气道高反应性。
在WT和ITK基因敲除小鼠中诱导实验性过敏性哮喘。分析气管对卡巴胆碱、乙酰胆碱和氯化钾的反应。还分析了过敏原激发小鼠对乙酰甲胆碱激发的气道高反应性，以及肺和支气管肺泡灌洗液中T(H)2细胞因子的信息和蛋白。
ITK基因敲除小鼠在过敏原激发之前和之后，体外对胆碱能激发的气管反应均降低。这些小鼠对过敏原激发的气道高反应性也降低，通过移植WT脾细胞或纯化的WT CD4+ T细胞可以挽救这种情况。这种降低的气道反应性优先伴随着肺中T(H)2细胞因子表达的降低。
我们的结果表明，酪氨酸激酶ITK及其在T细胞中的功能是抗哮喘药物的一个有吸引力的靶点。
调节ITK的表达或活性可能是阻断过敏性气道炎症的一种新策略。
