Screening Inhaled Allergen Challenge for Dermatophagoides Farinae

Asthma is an increasingly common chronic illness among children and adults, and allergen exposure is among the most common common triggers for asthma exacerbations. Exacerbations of allergic asthma are characterized by an early phase response (EPR), mediated by release of preformed mediators like histamine from mast cells, and a late phase response (LPR) 3-7 hours later mediated by chemokines and cytokines that attract leukocytes such as neutrophils and eosinophils to the airways, increase mucus production, trigger airway smooth muscle contraction, and result in airway constriction and airway hyperreactivity (AHR). The LPR does not occur in the absence of an EPR. The LPR is thought to be predominantly responsible for the symptoms associated with acute exacerbations of allergic asthma and is often used as the measure of efficacy in trials of asthma therapeutics.

This group has taken a particular interest in targeting an inflammatory cytokine, Interleukin-1β, involved in both the early and late phase asthmatic responses to inhaled allergen in allergic asthmatics. In the lung, interleukin 1 beta (IL-1β) is produced by numerous cell types (including epithelial cells, macrophages, neutrophils, eosinophils, and mast cells), where it signals through its receptor to induce transcription of pro-inflammatory genes (17-19). IL-1β is increased in bronchoalveolar lavage fluid from persons with symptomatic asthma vs. those with asymptomatic asthma; likewise, immunohistochemistry of bronchial biopsies of allergic asthmatics reveal increased expression of IL-1β in both bronchial epithelial cells and macrophages. Previous studies in animal and in vitro models demonstrate that IL-1β can directly impact three aspects of an airway inflammatory response: 1). granulocyte (neutrophil/eosinophil) recruitment; 2). non-specific (23, 24) and allergen-specific airway reactivity; and 3). production and clearance of airway mucous. Supporting literature and preliminary studies in human subjects further promote the study of IL-1 blockade for mitigating features of acute allergen-induced asthma exacerbation.

The role of IL-1 in allergen challenge models has not been fully defined. In a study examining 12 asthmatics allergic to D. farinae at this research center, we found that 9/12 asthmatics had a greater than 10% reduction in forced expiratory volume in 1 second (FEV1) after inhaled dust mite challenge. These individuals were considered responders. It was notable that when comparing post-allergen levels of cytokines between responders and non-responders there was a much greater concentration of IL-1β in post-challenge sputum from responders vs. nonresponders, Furthermore, within the responders, post challenge IL-1β also significantly correlated with sputum eosinophil concentrations (r=0.83, P<0.05) and neutrophil concentrations (r=0.89, P<0.05) 24 hours after allergen challenge. These data suggest that IL-1β may play a role in both immediate airway hyperresponsiveness and the late phase recruitment of inflammatory cells (neutrophils and eosinophils) after inhaled allergen challenge.

In order to better understand the role of IL-1β in allergen-induced airway inflammation, induced sputum will be obtained to determine if higher baseline sputum IL-1β concentrations or larger increases in IL-1β following allergen challenge impact non-specific airway hyperresponsiveness (via methacholine challenge), sputum granulocyte recruitment (neutrophil and eosinophil counts and exhaled nitric oxide (eNO), a marker of airway eosinophilia), or changes in expression of inflammatory or allergy-related genes. To this last point, little is known about the mechanisms contributing to response patterns in allergic asthmatics undergoing allergen challenge. Changes in gene expression occurring during the window of time between the EPR and LPR, as these expression changes may dictate whether or not a LPR occurs or to what extent it occurs.

The goal of this screening protocol is to identify subjects who exhibit both an EPR and LPR and who will be eligible for enrollment in the yet to be developed Il-1β protocols. Subjects will undergo a baseline methacholine challenge to establish reactivity, then allergen exposure, followed 24 hours later by methacholine challenge.