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  • Review Article
  • Published:

Targeting eosinophils in allergy, inflammation and beyond

Nature Reviews Drug Discovery volume 12, pages 117–129 (2013)Cite this article

Subjects

Key Points

  • 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.

Abstract

Eosinophils can regulate local immune and inflammatory responses, and their accumulation in the blood and tissue is associated with several inflammatory and infectious diseases. Thus, therapies that target eosinophils may help control diverse diseases, including atopic disorders such as asthma and allergy, as well as diseases that are not primarily associated with eosinophils, such as autoimmunity and malignancy. Eosinophil-targeted therapeutic agents that are aimed at blocking specific steps involved in eosinophil development, migration and activation have recently entered clinical testing and have produced encouraging results and insights into the role of eosinophils. In this Review, we describe recent advances in the development of first-generation eosinophil-targeted therapies and highlight strategies for using personalized medicine to treat eosinophilic disorders.

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Figure 1: Effector functions of eosinophils.
Figure 2: The effects of corticosteroids on eosinophils.
Figure 3: IL-5-mediated signalling.
Figure 4: Eosinophil priming results in amplified responses.
Figure 5: Subphenotyping patients with eosinophilia for personalized treatment plans.

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Acknowledgements

The authors thank S. Hottinger for editorial support and the following for support of their research programmes: the US National Institutes of Health (R01AI045898, R37AI045898, R01AI057803, R01AI061097, R01AI083450, R01DK076893, U01AI088806, U19AI070235, U19AI066738, P01HL076383 and K12HD028827); the US Department of Defense (W81XWH1010167); the CURED (Campaign Urging Research for Eosinophilic Disease) Foundation; the Buckeye Foundation; the Food Allergy Research & Education (FARE; formerly Food Allergy Initiative (FAI) and Food Allergy & Anaphylaxis Network (FAAN)); the Angels for Eosinophilic Research Alliance; and the Cincinnati Children's Hospital Medical Center.

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  1. Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, 45229, Ohio, USA

    Patricia C. Fulkerson & Marc E. Rothenberg

  2. Patricia C. Fulkerson & Marc E. Rothenberg

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Competing interests

M.E.R. is a consultant for Immune Pharmaceuticals and has an equity interest, has a royalty interest for reslizumab (Teva Pharmaceuticals) and is an inventor of subject-related patents owned by Cincinnati Children's Hospital. P.C.F. declares no competing financial interests.

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Glossary

Helminth infections

Infections with parasitic worms; helminth infections are the most common cause of eosinophilia worldwide, particularly in low-income countries. Infections with helminths can be transmitted via mosquito bites, by eating infected food, by drinking contaminated water and by walking on contaminated soil.

Churg–Strauss syndrome

A rare systemic necrotizing vasculitis that affects small to medium-sized vessels and is characterized by asthma, blood eosinophilia and eosinophil-rich granulomatous inflammation in affected tissues. First-line treatment involves the use of corticosteroids.

Hypereosinophilic syndrome

A heterogenous group of disorders characterized by a persistently elevated peripheral blood eosinophil count (> 1,500 eosinophils per mm3), typically without any recognizable cause.

Eosinophilic oesophagitis

A chronic antigen-induced disease characterized by symptoms of oesophageal dysfunction, evidence of eosinophil infiltration of at least 15 eosinophils per high-power microscopy field on oesophageal biopsy and the exclusion of other possible causes of oesophageal eosinophilia, especially oesophageal eosinophilia induced by gastroesophageal reflux disease.

Eotaxins

A subset of structurally related chemokines that bind to the eotaxin receptor (CC chemokine receptor 3) and are involved in selectively activating and chemoattracting eosinophils.

Respiratory burst

The rapid release of destructive reactive oxygen species from eosinophils and other immune cells that have an important role in the immune response to infection; this contributes to oxidative damage during inflammatory responses.

Atopic asthma

Also known as allergic asthma; a form of asthma that is characterized by recurrent attacks of difficulty in breathing with wheezing and inflammation and is caused by exposure to inhaled airborne allergens.

Periostin

An extracellular matrix protein that interacts with integrin molecules on epithelial and leukocyte cell surfaces. Periostin expression is induced by T helper 2 (TH2) cytokines such as interleukin-4 (IL-4) and IL-13. Periostin promotes allergic inflammation, including the accumulation of eosinophils in the skin.

Eosinopenia

A lower than expected number of eosinophils in the blood or tissue. Eosinopenia can be caused by stress reactions, bacterial infections and the use of corticosteroids.

Antisense oligonucleotide

A synthesized strand of nucleic acid (DNA or RNA) that is complementary to a specific mRNA. Antisense oligonucleotides bind to their target mRNA to promote degradation of the mRNA and prevent its translation, which can ultimately lead to decreased expression of a particular protein.

Splice-switching oligonucleotides

Oligonucleotides that target and bind to a particular mRNA and can be designed to promote favourable splice variants (rather than promoting degradation of the mRNA of targeted genes).

IL-1RL1

Interleukin-1 receptor-like 1; also known as ST2 protein. A component of the receptor for IL-33 that is widely expressed by innate immune cells and a subset of T cell lymphocytes.

Atopy

The predisposition to develop allergic hypersensitivity (that is, immunoglobulin E-mediated) reactions that can result from both hereditary and environmental components.

FEV1

Forced expiratory volume in 1 second; the maximal amount of air that an individual can forcefully exhale in 1 second as calculated during pulmonary function testing. A normal FEV1 is predicted based on height, weight and race. A lower than normal FEV1 is a marker of an obstructive process such as asthma.

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Fulkerson, P., Rothenberg, M. Targeting eosinophils in allergy, inflammation and beyond. Nat Rev Drug Discov 12, 117–129 (2013). https://doi.org/10.1038/nrd3838

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