Novel mechanisms of selective basophil regulation

Atopy is a frequent disorder resulting in clinical symptoms of rhinitis, conjunctivitis, bronchial asthma or dermatitis. A further group of diseases such as intrinsic asthma and aspirin sensitivity, resemble most aspects of allergy, but without a proven involvement of allergens. Most patients are affected for their entire life span, and no causal therapy is currently available, except in some cases by systemic desensitization with the respective allergen. Symptomatic therapy regimen are frequently ineffective or produce serious side-effects (e.g. corticosteroids). Historically, atopy was explained as allergen-induced degranulation of mast cells with subsequent release of the inflammatory mediator, histamine. Current view implicates a wide range of inflammatory cells acting together, among these macrophages, T-lymphocytes, and eosinophilic and basophilic granulocytes. The basophil, in particular, is emerging as a possible key player in allergy, since it accumulates at sites of allergen exposure, releases histamine and leukotriene C4, and produces large amounts of Interleukin (IL)-4 and IL-13, after allergen challenge. This suggests that basophils might be involved at various pathogenic steps of allergy and asthma, including early- and late-phase responses, airway hyperreactivity as well as the switch to IgE production. Therefore, pharmacological reduction of basophil recruitment into the tissue might disrupt the deleterious cascade of allergy at multiple sites. Migration of inflammatory cells from the circulation to sites of inflammation is directed by chemotactic cytokines (chemokines). Little is known at present about the pharmacological basis of selective basophil recruitment, which does not parallel the influx of other inflammatory cells. The aim of the study as proposed here is to identify novel mechanisms of basophil recruitment and characterize them as possible pharmacological targets. Two lines of investigation will be followed. First, we attempt to isolate novel basophil-specific chemo-attractants from human material. Second, the possible cooperative/synergistic effect of known chemokines and mediators on basophil function will be investigated. These studies will propose novel mechanisms of selective basophil recruitment, the pharmacological blockade of which might ultimately result in effective treatment of allergy and asthma.