Mapping the Kinetics of Cytokine Responses to Mechanical Stimulation of the Nose in Asthmatic, Allergic and Non-Allergic Subjects - A Pilot Study

Allergic rhinitis (AR) and allergic asthma are a common manifestations of Type I allergy, an IgE-mediated hypersensitivity disease estimated to affect as much as 40% of the global population . IgE is produced by B cells and binds to the surface of mast cells and basophils via its high affinity Fce receptor I (FceRI). Crosslinking of surface IgE by its specific allergen induces degranulation of the cells as well as release of inflammatory mediators. This process which develops over minutes leads to the typical ocular, nasal and pulmonary symptoms of AR and asthma such as itching, reddening of the eyes, runny and/or congested nose and wheezing due to air trapping as a result of lower airway obstruction. Some patients may also develop late phase reactions (LPR). These responses typically develop 2-6 hours after allergen exposure, peaking in intensity between 6-9 hours and are mostly characterised by tissue oedema which manifests as airflow obstruction in the airways.

Since the introduction of easy to use and highly absorptive mucosal fluid sampling devices the mediators involved in the immediate and late phase allergic responses and the kinetics of their release have become well characterised over the past few years. Efforts by Imperial College London and unpublished data from the investigators group in Vienna have shown that key mediators involved in the immediate phase include mast cell derived mediators, (Tryptase, PGD2), epithelial alarmins (IL-33, sST2), and complement (C3a, C4a, C5a, D-Dimer). Mediators involved in the late phase reactions also include alarmins (sST2, TSLP), Th2 cytokines (IL-4, IL-5, IL-13), neutrophil mediators (MMP-9) and eosinophil mediators (EDN).

However what has also recently become clear through placebo controlled studies is that some mediators are mechanically mediated (unpublished observations), being released into the extracellular environment as a result of the sampling process itself. This is of vital interest as understanding which cytokines are mechanical and which are allergen specific will help guide future studies attempting to target specific biomarkers for treatment or disease monitoring. In order to understand if the mechanical release plays any role in the pathological response to allergens different patient cohorts will need to be investigated to see if their responses differ in any way.

Rational of the Study

In light of this the investigators propose a study to investigate the effects of mucosal sampling on cytokine release from nasal epithelium. The investigators plan to sample different patient cohorts (allergic rhinitis, allergic asthma, non-allergic) to see how mechanical effects are influenced by sampling and allergic or non-allergic status. By including 10 patients in each group the investigators hope to establish a range of "normal" for mechanical release of allergen relevant cytokines in each study group which will help inform future studies investigating allergen specific responses. In order to map both the symptomatic and objective responses to airway sampling, symptom scores and airway flow meters will be employed. To map the kinetics of responses the participants will undergo a mucosal sampling time course over the course of an 8 hour period on a single day. As no interventional substances are being given, this study will carry very low risk to the individuals involved while shedding important light on the epithelial responses to mechanical manipulation.