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Outcomes and Interpretation of Results

The allergen challenge model has been valuable in human asthma research for assessing the mechanisms of variable airflow obstruction, airway hyperresponsiveness, and cellular inflammation. Measurements of airway tone are evaluated by examining the magnitude of the EAR and LAR expressed as percent fall in FEV1 from prechallenge baseline. The EAR and LAR can also be expressed as AUC of the percent fall in FEV1 x time curve. Inhaled allergen is shown to shift the dose-response to direct stimuli such as methacholine and histamine, and this is likely related to the allergen-induced accumulation of inflammatory cells, including eosinophils, basophils, and mast cells in the airways, which can also be counted in the bronchial biopsies, bronchoalveolar lavage, and samples of induced sputum (Gauvreau et al. 2000a; Gauvreau and Evans 2007; Diamant et al. 2013).

The high reproducibility and clinical relevance of allergen-induced airway responses has positioned the allergen challenge model as an invaluable tool for assessing the efficacy of current and investigational anti-inflammatory therapies for the treatment of asthma (Boulet et al. 2007). In a crossover study design, as few as 8 subjects can be used to detect a 50% inhibition of the EAR and LAR (Inman et al. 1995; Gauvreau et al. 1999b). The allergen challenge model was initially used to demonstrate the efficacy of commonly used asthma treatments, including ICSs, antileukotrienes, and short-acting beta agonists.

Many studies have been conducted to evaluate the effects of anti-inflammatory therapies on allergen-induced responses. Early studies demonstrated very clear inhibition of the LAR with single dose or regular treatment with inhaled budesonide (Gauvreau et al. 1996; Kidney et al. 1997), and ICSs have also been shown to significantly shift the allergen PC15 (Cockcroft et al. 1995). Subsequent studies sought to utilize the allergen challenge model to investigate the anti-inflammatory properties of ICSs, finding that in addition to inhibition of the EAR and LAR, ICSs reduced the number of eosinophils and their progenitors in the airways, circulation, and bone marrow (Gauvreau et al. 1996; Sehmi et al. 1997; Wood et al. 1999, 2002; Gauvreau et al. 2000b) (Figure 10.7). The allergen challenge model has been used to generate steroid dose-response (Inman et al. 2001), to compare other therapies to corticosteroids as “gold standard” (Leigh et al. 2002; Duong et al. 2007), and to evaluate new therapeutics acting through the glucocorticoid receptor (Gauvreau et al. 2015).

In the studies of bronchodilators, surprising results were discovered when evaluating the effects of short-acting beta agonists on allergen-induced responses. In a study conducted by Cockcroft, salbutamol treatment, a regularly inhaled p2 agonist to reverse bronchoconstriction, was tested using the allergen inhalation challenge model. Since allergen is a more relevant environmental stimulus compared to chemical stimuli such as AMP, histamine, and methacholine, the inhaled allergen model was a highly relevant model to test the treatment effects of regular dosing of salbutamol compared to placebo in allergic asthmatics (Cockcroft 1993). Cockcroft reports that following regular salbutamol treatment, there was a significant decrease in the protective effect on both the methacholine and allergen PC20, where the allergic asthmatics tolerated lower levels of methacholine and allergen after salbutamol treatment compared to placebo (Cockcroft 1993). These findings highlight the detrimental effects of continual, regular use of inhaled p2 agonist. In support, Gauvreau et al. also showed that that allergen-induced LAR was far worsened in allergic asthmatics treated with albuterol after allergen inhalation challenge compared to placebo (Gauvreau et al. 1997). Further supporting the notion that regular use of inhaled p2 agonist has detrimental effects on allergen sensitivity, Gauvreau et al. showed that in albuterol-treated asthmatics, but not placebo, there were increased airway hyperreactivity (decreased methacholine PC20), increased sputum eosinophilia, and increased sputum ECP levels after allergen inhalation challenge. These studies demonstrated that regular use of salbutamol renders the airways more responsive to direct and indirect stimuli in terms of bronchoconstriction and inflammation.

In addition to testing the efficacy and inflammatory profiles of known asthma therapeutics using the allergen inhalation challenge model, novel therapeutics are also evaluated. Novel anti-inflammatory therapies such as anti-IL-13 have been tested in this model, where inhibition of the LAR by anti-IL-13 (Gauvreau et al. 2011) provides key information supporting further development of drugs targeting the IL-13 pathway. However, there are other biologic targets that have shown efficacy in the clinical treatment of allergic asthmatics, which have been tested using the allergen inhalation challenge model, including anti-IgE (omalizumab, also commercially known as Xolair) and anti-TSLP.

B cell production of IgE is an important therapeutic target, particularly in IgE-mediated disease, due to their involvement in initiating the allergic cascade (Platts-Mills 2001). Antibodies, like IgE, have been implicated in diseases since the 1890s and antibody-producing B cells were first reported in 1956 by Glick et al., when they found that cells from the bursa of Fabricius in young chickens produced antibodies early in their development to aid in disease resistance (Glick et al. 1956). As already established earlier, in the context of allergic asthma, IgE have large roles in disease pathogenesis (Smurthwaite et al. 2001). Historically, IgE was first reported on by Lichtenstein et al. (1966) and Ishizaka et al. (1966) in 1966. Over 50 years after the discovery of IgE, researchers have shown that IgE is increased in individuals with atopic diseases (Stone et al. 2010), especially in the airways and peripheral compartments after allergen inhalation challenge (Wilson et al. 2002; Gauvreau et al. 2014c). In a seminal study conducted by Boulet et al., anti-IgE treatment of allergic asthmatics was shown to have drastic improvements on allergen PQFEVj and free serum IgE. Furthermore, anti-IgE treatment demonstrated inhibitory effects on allergen-induced EAR, which made it a promising therapeutic to further study on allergic asthmatics, particularly using the allergen inhalation challenge model.

Several therapies have been developed to reduce the level of IgE, which have utilized the allergen inhalation challenge model as their proof of concept model. Currently, omalizumab is a monoclonal antibody against IgE that is able to bind free IgE in serum and on the surface of B cells (Holgate et al. 2005; Chan et al. 2013; Nyborg et al. 2015). In the allergen challenge model, it has shown efficacy in improving asthma symptoms and reducing exacerbations (O’Byrne et al. 1987; Fahy et al. 1997). In mechanistic studies using the allergen challenge model, the treatment with omalizumab inhibited both the EAR and LAR and decreased eosinophil levels in sputum (Fahy et al. 1997; Djukanovic et al. 2004).

Due to the success of omalizumab, new systemic approaches for reducing circulating levels of IgE have been further pursued and evaluated. A novel anti-IgE therapeutic, ligelizumab (QGE031), has higher affinity for IgE compared to omali- zumab, resulting in increased suppression of IgE-receptor complex formation (Arm et al. 2014) and providing enhanced protection compared to omalizumab (Oliveria et al. 2014). Furthermore, Gauvreau et al. showed that ligelizumab was superior to omalizumab at improving PC15FEV1 at both 72 and 240 mg doses of ligelizumab treatment (Gauvreau et al. 2014). In addition to the improvement in bronchial provocation testing, ligelizumab also demonstrated suppression of free serum IgE, surface IgE receptors on basophils (FceRI), and skin prick test responses.

Unlike omalizumab and ligelizumab, there have been advances in specifically targeting IgE expressed on the surface of memory B cells. Gauvreau et al. used monoclonal antibody, which targeted M1-prime, a specific epitope on IgE bound on the surface of B cells, to specifically target the depletion of IgE+ B cells. The treatment with anti-M1-prime antibody (quilizumab) reduced total IgE and airway eosinophils, accompanied by blunted EAR, but not LAR to inhaled allergen (Gauvreau et al. 2014c).

In addition to omalizumab, ligelizumab, and quilizumab, there are also other approaches that have been tested using the allergen inhalation challenge model, which indirectly aim to reduce the synthesis of IgE by regulating B cell functions in subjects with allergic asthma. Briefly, the blockade of OX40L was found by Gauvreau et al. to decrease total and allergen-specific IgE in the circulation compared to placebo (Gauvreau et al. 2014), and these decreases were sustained over 250 days after treatment. Additionally, anti-OX40L treatment also reduced eosinophil levels in the sputum. However, there were no treatment effects on the EAR or LAR comparing anti-OX40L and placebo.

Elucidating the inflammatory pathways leading to the EAR and LAR using the allergen challenge model is crucial in discovering the critical pathways for the treatment of allergic asthma. For example, targeting TSLP, an upstream alarmin cytokine capable of initiating the inflammatory cascade, using a monoclonal antibody would be a promising upstream target with the potential of dampening downstream inflammatory processes (Dahlen 2014). A study by Gauvreau et al. evaluated allergen- induced asthmatic responses after treatment with anti-TSLP (AMG 157) (Gauvreau et al. 2014d). Remarkably, the treatment with anti-TSLP attenuated both the EAR and LAR compared to placebo (Gauvreau et al. 2014d). Furthermore, blood and sputum eosinophils and the fraction of exhaled nitric oxide (FENO) were also decreased after anti-TSLP treatment compared to placebo (Gauvreau et al. 2014d). Taken together, anti-TSLP attenuated allergen-induced bronchoconstriction and hallmark indices characterizing airway inflammation before and after allergen inhalation challenge.

As discussed earlier, the allergen challenge model is particularly useful for testing new therapeutics targeting type 2 inflammation. Overall, the allergen challenge model has an excellent negative predictive value for investigational therapies, which is an important consideration during drug development, thus highlighting the utility of the allergen inhalation challenge in early-phase clinical trials and the testing efficacy of a treatment in a disease.

 
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