Experimental approaches to evaluate respiratory allergy in animal models

Asthma is defined as a chronic disease of the entire lung and asthma attacks may either be immediate, delayed or dual in onset. Allergic asthma is a complex chronic inflammatory disease of the airways and its etiology is multifactorial. It involves the recruitment and activation of many inflammatory and structural cells, all of which release mediators that result in typical pathological changes of asthma. A wealth of clinical and experimental data suggests that allergic asthma is due to an aberrant lung immune response mediated through T-helper type 2 (Th2) cells and associated cytokine-signaling pathways. The pathology of asthma is associated with reversible narrowing of airways, associated with prominent features that involve structural changes in the airway walls and extracellular matrix remodeling including abnormalities of bronchial smooth muscle, eosinophilic inflammation of the bronchial wall, hyperplasia and hypertrophy of mucous glands. The primary objective of respiratory allergy tests is to determine whether a low-molecular-weight chemical (hapten) or high-molecular-weight compound (antigen) exhibits sensitizing properties to the respiratory tract. This may range from reactions occurring in the nose (allergic rhinitis), in the bronchial airways (i.e., allergic bronchitis, asthma) or alveoli (e.g., hypersensitivity pneumonitis). Current assays utilize several phases, viz. an induction phase, which includes multiple exposures to the test compound (sensitization) via the respiratory tract (e.g., by intranasal or intratracheal instillations), by inhalation exposures or by dermal contact, and a single or multiple challenge or elicitation phase. The challenge can either be with the chemical (hapten), the homologous protein conjugate of the hapten or the antigen. The choice depends both on the irritant potency and the physical form (vapor, aerosol) of the hapten. The appropriate selection of concentrations (dosages) both for the induction and elicitation of respiratory allergy appears to be paramount for the outcome of test. Endpoints to characterize positive response range from the induction of immunoglobulins, cytokine or lymphokine patterns in serum (or the lung) to (patho-)physiological reactions typifying asthma. None of the currently applied animal models duplicate all features of human asthma. Accordingly, the specific pros and cons of the selected animal model, including protocol variables, animal species and strain selected, must be interpreted cautiously in order to arrive at a meaningful extrapolation for humans.