Targeting eosinophils in allergy, inflammation and beyond

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Abstract
The activation of eosinophils leads to the release of preformed and newly synthesized products including cytokines, chemokines, lipid mediators and cytotoxic granule proteins that can initiate, escalate and sustain local inflammatory and remodelling responses. Eosinophil secondary granules are primarily composed of highly charged basic proteins, including eosinophil granule major basic proteins, eosinophil cationic protein, eosinophil-derived neurotoxin and eosinophil peroxidase. In addition, eosinophil granules contain a plethora of preformed cytokines, chemokines, enzymes and growth factors, resulting in the diverse biological activity of eosinophils in infection and inflammation. Although glucocorticoids are very effective at reducing eosinophil numbers in the blood and tissue, patients often experience harmful side effects and develop resistance. Therapy directed against the eosinophil growth factor interleukin-5 (IL-5) has been tested in clinical trials for efficacy in several eosinophil-associated disorders and looks promising. However, the reduction in tissue eosinophilia and improvement in symptoms has been variable and dependent on patient phenotypes (subgroups). Thus, additional approaches for selecting patients and new drugs based on an improved understanding of the mechanism of eosinophilia and the effector functions of eosinophils are needed. Preclinical studies suggest that inhibition of eosinophil migration from the bloodstream into tissues has therapeutic potential, but there has been limited clinical success to date with current targets and approaches. The lack of effectiveness may be due to the complex regulation of eosinophil recruitment into inflammatory tissues. Preclinical studies that are focused on promoting eosinophil apoptosis support continued investigations into sialic acid-binding immunoglobulin-like lectin 8 (SIGLEC-8)-targeted therapies, as engagement of SIGLEC-8 results in selective apoptosis of eosinophils. The treatment of patients with allergic asthma using omalizumab, a recombinant monoclonal antibody that binds to immunoglobulin E, results in a reduction in blood and tissue eosinophilia through an as yet unknown mechanism. Studies that are focused on the mechanism of this reduction are needed and may yield new therapeutic targets. Post-hoc analyses of clinical trial results have emphasized the importance of subphenotyping patients to identify those patients who are likely to receive the most therapeutic benefit from a specific agent. There is a need to identify subgroups of patients with eosinophilic disorders to predict treatment responses on the basis of a patient's genetics or gene expression profiles of affected organs in order to tailor the therapy for their eosinophil-associated disease.

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