Differential Gene Expression in Lung and Peripheral Blood After Inhaled Allergen Challenge

Overview

The purpose of this study is to identify the genes in important airway cells that are specifically expressed following inhalation of house dust mite allergen among study subjects with either allergic asthma or healthy normal phenotypes. This approach is designed to identify novel genes associated with both asthma pathogenesis (differentially expressed in the exposure-response study) and asthma susceptibility (genetically associated with asthma in a linkage/association study) for drug targets.

The purpose of this study is to identify the genes in airway epithelial and BAL cells that are differentially expressed following inhalation of house dust mite allergen among study subjects with allergic asthma and normal phenotypes. This approach is designed to identify novel genes associated with both asthma pathogenesis (differentially expressed in the exposure-response study) and asthma susceptibility (genetically associated with asthma in a linkage/association study). Patients with asthma and allergic rhinitis have long been known to have positive skin test responses to house dust. In the 1960's it was shown that the dust mite was the most important source of allergen in house dust. Techniques for growing dust mites in the laboratory enabled the preparation of dust mite allergen extracts. Identification of the major allergens of dust mite along with specific skin test methodology has resulted in standardized dust mite allergen extracts for diagnostic and therapeutic use. Numerous epidemiologic studies have demonstrated the importance of sensitization to dust mite as risk factors for asthma and allergic rhinitis symptoms. Administration of dust mite by inhalation is considered investigational. However, numerous studies demonstrate the safety of allergen inhalation in well characterized subjects. A recent NHLBI/NIAID Workshop summarized evidence of the safety and utility of research bronchoprovocation and bronchoscopy studies in subjects with chronic airway diseases. Bronchoprovocation challenge has emerged as an important tool to understand the environmental factors involved in the asthmatic response. Airway hyperresponsiveness (AHR), an exaggerated bronchoconstrictor response to a variety of stimuli, is a prominent characteristic of asthma. Importantly, AHR to methacholine is correlated with symptoms and severity of disease. Although the mechanisms underlying AHR are poorly understood, it is believed to result, at least in part, from airway inflammation. Bronchoprovocation is a well-established method to detect and quantify AHR and to obtain insights into the mechanisms associated with this pathophysiologic entity. Increased airway response after allergen inhalation parallels the subsequent inflammatory reaction, suggesting that the allergen-induced inflammation has direct effects on mechanisms of airway responsiveness. Moreover, the techniques and applications of bronchoprovocation, both for testing nonspecific airway responsiveness and specific allergen challenge, have been well defined. Therefore it is evident that bronchoprovocation testing is considered useful and safe, and also likely to yield important insights into the pathogenesis of asthma. Bronchoscopic airway sampling for investigational purposes has also yielded important insights regarding the pathogenesis of asthma and related airway disorders. Bronchoalveolar lavage (BAL) and endobronchial brush biopsies have emerged as the most widely used invasive research tools to assess inflammation and tissue remodeling in airway and interstitial lung diseases. Such procedures allow airway inflammatory and epithelial cells, proteins and other molecules of interest to be isolated in vivo in a manner that is critical to understanding the complex nature of asthma and other airway disorders. Numerous reports have attested to the safety of bronchoscopy including BAL and brush biopsy; these reports have been reviewed recently in a joint publication between the NHLBI and NIAID. So not only is bronchoscopic airway sampling important scientifically, but it is considered appropriate for research use in normal and asthmatic subjects. The combination of bronchoprovocation and bronchoscopic airway sampling thus seems ideally suited to understand the complex host-environment interactions of asthma: the environmental stimulus response in a specified host could trigger a number of reactions that could be measured in the distal airways and airway epithelia.

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