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Medical Journal Review

June 2016

WAO Reviews - Editors' Choice

The Editors select articles for their importance to clinicians who care for patients with asthma and allergic/immunologic diseases, and whenever possible they seek articles that everyone can access freely. The Editors’ Choice comes to you each month from Juan Carlos Ivancevich, MD, WAO Web Editor-in-Chief, and summary author, John J. Oppenheimer, MD, FACAAI, FAAAAI, WAO Reviews Editor.

1. Allergen-associated immunomodulators: modifying allergy outcome

Gómez-Casado C, Díaz-Perales A. Allergen-associated immunomodulators: modifying allergy outcome. Archivum Immunologiae et Therapiae Experimentalis 2016; published online ahead of print, May 13. (doi: 10.1007/s00005-016-0401-2)


Understanding the mechanism of how a protein becomes an allergen has been a major focus in our study of allergic disease. Although most studies regarding allergen immunogenicity have focused on structural properties of proteins, it is increasingly clear that allergenicity cannot be determined solely based on structural features of allergenic proteins. Allergenic moieties are complex mixtures of proteins, carbohydrates and lipids. As a result, attention has lately been directed towards allergen-associated molecules, beyond proteins, that may exhibit immune-regulatory properties. This review by Go´mez-Casado and Dı´az-Perales examines how non-protein molecules accompanying the allergen can modulate allergic responses.

2. Epithelium-generated neuropeptide Y induces smooth muscle contraction to promote airway hyperresponsiveness

Li S, Koziol-White C, Jude J, Jiang M, Zhao H et al. Epithelium-generated neuropeptide Y induces smooth muscle contraction to promote airway hyperresponsiveness. The Journal of Clinical Investigation 2016; 126(5): 1978-1982. (doi: 10.1172/JCI81389)

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Asthmatic patients can be divided into those with or without a Th2 predominant immune response. Unfortunately, current therapies have little effect on non-Th2 mediated disease, and the mechanisms that drive this type of asthma are not well understood. It is often this phenotype of asthmatic that have the greatest difficulty in attaining control.  In this study by Li et al., the authors give us some direction for future exploration of this subtype of asthmatic. They demonstrated that loss of the transcription factors forkhead box P1 (Foxp1) and Foxp4 (which are critical for lung epithelial development) in the adult airway epithelium evokes a non-Th2 asthma phenotype that is characterized by airway hyperresponsiveness (AHR) without eosinophilic inflammation. Further, they demonstrated through transcriptome analysis that loss of Foxp1 and Foxp4 expression induces ectopic expression of neuropeptide Y (Npy), which has been reported to be present in the airways of asthma patients, but whose importance in disease pathogenesis remains unclear. Finally, they showed that treatment of human lung airway explants with recombinant NPY increased airway contractility; while, loss of Npy in Foxp1- and Foxp4-mutant airway epithelium rescued the AHR phenotype. Together, these studies highlight the importance of paracrine signals from the airway epithelium to the underlying smooth muscle to induce AHR and suggest that therapies targeting epithelial induction of this phenotype may prove useful in treatment of non-eosinophilic asthma. 

3. Biodegradable antigen-associated PLG nanoparticles tolerize Th2-mediated allergic airway inflammation pre- and postsensitization

Smarr CB, Yap WT, Neef TP, Pearson RM, Hunter ZN et al. Biodegradable antigen-associated PLG nanoparticles tolerize Th2-mediated allergic airway inflammation pre- and postsensitization. Proceedings of the National Academy of Sciences of the United States of America 2016; 113(8): 5059-5064. (doi:10.1073/pnas.1505782113)


As we know all too well, specific immunotherapy (SIT) is a useful intervention, via its ability to dampen the Th2 response. However, it requires a long period of dose escalation with soluble antigen (Ag) and carries a significant risk of adverse reactions, particularly in highly sensitized patients who stand to benefit most this treatment. In light of these issues, the development of safer, more efficient methods to induce Ag-specific immune tolerance is critical to advancing allergy treatment. In this study by Smarr and colleagues, they explore the use of antigen associated nanoparticles (Ag-NPs) (which have been used to prevent and treat Th1/Th17-mediated autoimmune disease), to determine if they could attain induction of tolerance in a murine model of Th2-mediated ovalbumin/alum-induced allergic airway inflammation.

The authors demonstrated that progression of antigen-conjugated NPs made of biodegradable poly(lactide-co-glycolide) toward PLG(Ag) as a biodegradable Ag carrier platform resulted in a safe and effective inhibition of allergic airway inflammation in an animal model with established Th2 sensitization. Specifically, they showed that antigen-conjugated polystyrene (Ag-PS) NPs, although effective for the prophylactic induction of tolerance, could induce anaphylaxis in pre-sensitized mice. Antigen-conjugated NPs made of biodegradable poly(lactide-co-glycolide) (Ag-PLG) are similarly effective prophylactically, are well tolerated by sensitized animals, but could only partially inhibit Th2 responses when administered therapeutically. While PLG NPs containing encapsulated antigen [PLG(Ag)] were well tolerated and also effectively inhibited Th2 responses and airway inflammation both prophylactically and therapeutically. This represents an exciting direction in our quest for a safer form of immunotherapy.

4. Assessing biomarkers in a real-world severe asthma study (ARIETTA)

Buhl R, Korn S, Menzies-Gow A, Aubier M, Chapman KR et al. Assessing biomarkers in a real-world severe asthma study (ARIETTA). Respiratory Medicine 2016; 115: 7-12. (doi:10.1016/j.rmed.2016.04.001)

Full Text, Open Access

The prognostic value of asthma biomarkers in routine clinical practice is not fully understood. To better understand their role, the ARIETTA study is being performed.  In this paper, the authors share with us the design of this ongoing, prospective, longitudinal, international, multicenter real-world study designed to assess the relationship between asthma biomarkers and disease-related health outcomes. This international trial will enroll and follow for 52 weeks approximately 1200 severe asthma patients (treated with daily high dose inhaled corticosteroids and at least 1 second controller medication). In this real-world study, patients will be treated according to the investigator's routine clinical practices and no treatment regimen will be implemented as part of the trial. At baseline and again at 26 and 52 weeks, FEV1, FeNO, serum periostin, blood eosinophil count and serum IgE will be measured.  Asthma-related symptoms and quality of life questionnaires will be administered at the visits and during telephone interviews at weeks 13 and 39. Data regarding medication use, asthma exacerbations, asthma-related healthcare utilization and events raising safety concerns will also be collected.

Many of us cannot wait for the results. This study is unique in both its scope and scale and it is hoped that it will address fundamental unanswered questions regarding asthma biomarkers and their interrelationship, as well as predict deviations in the course of asthma in a real-world setting.

5. Depletion of major pathogenic cells in asthma by targeting CRTh2

Huang T, Hazen M, Shang Y, Zhou M, Wu X. Depletion of major pathogenic cells in asthma by targeting CRTh2. JCI Insight 2016; 1(7). (doi: 10.1172/jci.insight.86689)

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Eosinophilic inflammation and Th2 cytokine production are central to the pathogenesis of asthma.

Agents that target either eosinophils or single Th2 cytokines have shown benefits in subsets of biomarker-positive asthmatic patients. As there may be redundancy, as well as multiple inflammatory pathways, it follows that more broadly effective treatment or disease-modifying effects may be achieved by eliminating more than one inflammatory stimulator. In this study by Huang et al., the authors present a strategy to concomitantly deplete Th2 T cells, eosinophils, basophils, and type-2 innate lymphoid cells (ILC2s) through the generation of monoclonal antibodies with enhanced effector function (19A2) that target CRTh2 present on all 4 cell types. Using human CRTh2 (hCRTh2) transgenic mice that mimic the expression pattern of hCRTh2 on innate immune cells but not Th2 cells, they demonstrated that anti-hCRTh2 antibodies specifically eliminate hCRTh2+ basophils, eosinophils, and ILC2s from lung as well as lymphoid organs in models of asthma. Innate cell depletion was accompanied by a decrease of several Th2 cytokines and chemokines. hCRTh2-specific antibodies were also active on human Th2 cells in vivo in a human Th2-PBMC-SCID mouse model.  The authors note that depletion of hCRTh2+ basophils, eosinophils, ILC2, and Th2 cells with h19A2 hCRTh2–specific antibodies may be a novel and more efficacious treatment for asthma, but future studies with anti-CRTh2 antibodies will specifically need to be evaluated regarding their safety, pharmacodynamics as well pharmacokinetic characteristics.