Background: Patients with allergic asthma have symptoms of a predominant T H2 response, including airway eosinophilic inflammation and increased mucous production in the lungs. This accompanies increased airways responsiveness, which can be life threatening. Because T H2 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. Objective: 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. Methods: 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 H2 cytokine message and protein. Results: 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 H2 cytokines in the lungs. Conclusion: Our results indicate that the tyrosine kinase ITK and its function in T cells represent an attractive target for antiasthmatic drugs. Clinical implications: Modulating the expression or activity of ITK may be a novel strategy to block allergic airway inflammation.
All Science Journal Classification (ASJC) codes
- Immunology and Allergy