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Pfaar O, Creticos PS, Kleine-Tebbe J, Canonica GW, Palomares O, Schülke S. One Hundred Ten Years of Allergen Immunotherapy: A Broad Look Into the Future. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE 2021; 9:1791-1803. [PMID: 33966868 DOI: 10.1016/j.jaip.2020.12.067] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 12/14/2020] [Accepted: 12/18/2020] [Indexed: 12/15/2022]
Abstract
Allergen immunotherapy (AIT) is the only disease-modifying treatment option for patients with type 1-mediated allergic diseases such as allergic rhinitis/rhinoconjunctivitis with/without allergic asthma. Although many innovations have been developed since the first clinical report of Noon et al in 1911, the improvement of clinical efficacy and tolerability of this treatment is still an important unmet need. Hence, much progress has been made in the characterization of the cell types, cytokines, and intracellular signaling events involved in the development, maintenance, and regulation of allergic reactions, and also in the understanding of the mechanisms of tolerance induction in AIT. This comprehensive review aims to summarize the current innovative approaches in AIT, but also gives an outlook on promising candidates of the future. On the basis of an extensive literature review, integrating a clinical point of view, this article focuses on recent and future innovations regarding biologicals, allergen-derived peptides, recombinant allergens, "Toll"-like receptor agonists and other adjuvants, and novel application routes being developed for future AIT.
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Affiliation(s)
- Oliver Pfaar
- Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Marburg, Philipps-Universität Marburg, Marburg, Germany.
| | - Peter S Creticos
- Division of Allergy & Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, Md; Creticos Research Group, Crownsville, Md
| | - Jörg Kleine-Tebbe
- Allergy & Asthma Center Westend, Outpatient & Clinical Research Center, Hanf, Ackermann & Kleine-Tebbe, Berlin, Germany
| | - Giorgio Walter Canonica
- Personalized Medicine Asthma & Allergy Clinic, Humanitas University & Research Hospital-IRCCS, Milano, Italy
| | - Oscar Palomares
- Department of Biochemistry and Molecular Biology, School of Chemistry, Complutense University, Madrid, Spain
| | - Stefan Schülke
- Vice Presidents Research Group, Paul-Ehrlich-Institut, Langen, Germany
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Agache I, Annesi‐Maesano I, Bonertz A, Branca F, Cant A, Fras Z, Ingenrieth F, Namazova‐Baranova L, Odemyr M, Spanevello A, Vieths S, Yorgancioglu A, Alvaro‐Lozano M, Barber Hernandez D, Chivato T, Del Giacco S, Diamant Z, Eguiluz‐Gracia I, Wijk RG, Gevaert P, Graessel A, Hellings P, Hoffmann‐Sommergruber K, Jutel M, Lau S, Lauerma A, Maria Olaguibel J, O'Mahony L, Ozdemir C, Palomares O, Pfaar O, Sastre J, Scadding G, Schmidt‐Weber C, Schmid‐Grendelmeier P, Shamji M, Skypala I, Spinola M, Spranger O, Torres M, Vereda A, Bonini S. Prioritizing research challenges and funding for allergy and asthma and the need for translational research-The European Strategic Forum on Allergic Diseases. Allergy 2019; 74:2064-2076. [PMID: 31070805 DOI: 10.1111/all.13856] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Revised: 05/02/2019] [Accepted: 05/05/2019] [Indexed: 02/07/2023]
Abstract
The European Academy of Allergy and Clinical Immunology (EAACI) organized the first European Strategic Forum on Allergic Diseases and Asthma. The main aim was to bring together all relevant stakeholders and decision-makers in the field of allergy, asthma and clinical Immunology around an open debate on contemporary challenges and potential solutions for the next decade. The Strategic Forum was an upscaling of the EAACI White Paper aiming to integrate the Academy's output with the perspective offered by EAACI's partners. This collaboration is fundamental for adapting and integrating allergy and asthma care into the context of real-world problems. The Strategic Forum on Allergic Diseases brought together all partners who have the drive and the influence to make positive change: national and international societies, patients' organizations, regulatory bodies and industry representatives. An open debate with a special focus on drug development and biomedical engineering, big data and information technology and allergic diseases and asthma in the context of environmental health concluded that connecting science with the transformation of care and a joint agreement between all partners on priorities and needs are essential to ensure a better management of allergic diseases and asthma in the advent of precision medicine together with global access to innovative and affordable diagnostics and therapeutics.
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Affiliation(s)
| | - Isabella Annesi‐Maesano
- Department of Epidemiology of Allergic and Respiratory Diseases Medical School Saint Antoine, IPLESP, INSERM and Sorbonne Université Paris France
| | - Andreas Bonertz
- Federal Agency for Vaccines and Biomedicines Paul‐Ehrlich‐Institut Langen Germany
| | - Francesco Branca
- Department of Nutrition for Health and Development Geneva Switzerland
- WHO/HQ Geneva Switzerland
| | - Andrew Cant
- University of Newcastle Upon Tyne Newcastle upon Tyne UK
- European Society for Immunodeficiencies Geneva Switzerland
| | - Zlatko Fras
- Division of Medicine University Medical Centre Ljubljana Ljubljana Slovenia
- Medical Faculty University of Ljubljana Ljubljana Slovenia
- UEMS ‐ Union Europeenne des Medecins Specialistes/European Union of Medical Specialists Brussels Belgium
| | | | - Leyla Namazova‐Baranova
- Department of Pediatrics Russian National Research Medical University of MoH RF Moscow Russia
- Department of Pediatrics Central Clinical Hospital of MoSHE (Ministry of Science and High Education) Moscow Russian Federation
| | - Mikaela Odemyr
- European Federation of Allergy and Airways Diseases Patients’ Associations (EFA) Brussels Belgium
| | - Antonio Spanevello
- Dipartimento di Medicina e Chirurgia, Malattie dell'Apparato Respiratorio Università degli Studi dell'Insubria Varese – Como Italy
- Dipartimento di Medicina e Riabilitazione Cardio Respiratoria, U.O. di Pneumologia Riabilitativa Istituti Clinici Scientifici Maugeri, IRCCS Tradate Tradate Italy
| | - Stefan Vieths
- Federal Agency for Vaccines and Biomedicines Paul‐Ehrlich‐Institut Langen Germany
| | - Arzu Yorgancioglu
- Department of Pulmonology Celal Bayar University School of Medicine Manisa Turkey
| | - Montserat Alvaro‐Lozano
- Pediatric Allergy and Clinical Immunology Department Hospital Sant Joan de Déu Barcelona Barcelona Spain
| | - Domingo Barber Hernandez
- Department of Basic Medical Sciences, School of Medicine Universidad CEU San Pablo Madrid Spain
- RETIC ARADYAL RD16/0006/0015, Instituto de Salud Carlos III Madrid Spain
| | - Tomás Chivato
- School of Medicine University CEU San Pablo Madrid Spain
| | - Stefano Del Giacco
- Department of Medical Sciences and Public Health University of Cagliari Cagliari Italy
| | - Zuzana Diamant
- Department of Respiratory Medicine & Allergology, Institute for Clinical Science, Skane University Hospital Lund University Lund Sweden
- Department of Respiratory Medicine, First Faculty of Medicine Charles University and Thomayer Hospital Prague Czech Republic
| | - Ibon Eguiluz‐Gracia
- Allergy Unit IBIMA, Regional University Hospital of Malaga, UMA Malaga Spain
- ARADyAL Network RD16/0006/0001, Carlos III Health Institute Madrid Spain
| | - Roy Gert Wijk
- Section of Allergology, Department of Internal Medicine Erasmus Medical Center Rotterdam the Netherlands
| | - Philippe Gevaert
- Department of Otorhinolaryngology‐Head and Neck Surgery, Upper Airways Research Laboratory Ghent University Ghent Belgium
| | - Anke Graessel
- Allergy Therapeutics Worthing UK
- Bencard Allergie GmbH Munich Germany
| | - Peter Hellings
- Department of Otorhinolaryngology‐Head and Neck Surgery, Upper Airways Research Laboratory Ghent University Ghent Belgium
- Department of Otorhinolaryngology‐Head and Neck Surgery UZ Leuven Leuven Belgium
- Department of Otorhinolaryngology Academic Medical Center Amsterdam The Netherlands
| | | | - Marek Jutel
- Department of Clinical Immunology Wroclaw Medical University Wroclaw Poland
- “ALL‐MED” Medical Research Institute Wroclaw Poland
| | - Susanne Lau
- Department for Pediatric Pneumology, Immunology and Intensive Care Charité Universität Medizin Berlin Germany
| | - Antti Lauerma
- Dermatology and Allergology Helsinki University Hospital and University of Helsinki Helsinki Finland
| | | | - Liam O'Mahony
- Departments of Medicine and Microbiology APC Microbiome Ireland, National University of Ireland Cork Ireland
| | - Cevdet Ozdemir
- Department of Pediatric Basic Sciences, Institute of Child Health Istanbul University Istanbul Turkey
- Department of Pediatrics, Division of Pediatric Allergy & Immunology, Istanbul Faculty of Medicine Istanbul University Istanbul Turkey
| | - Oscar Palomares
- Department of Biochemistry and Molecular Biology, School of Chemistry Complutense University of Madrid Madrid Spain
| | - Oliver Pfaar
- Department of Otorhinolaryngology, Head and Neck Surgery, Section of Rhinology and Allergy, University Hospital Marburg Philipps‐Universität Marburg Marburg Germany
| | - Joaquin Sastre
- Department of Allergy Fundación Jimenez Diaz Madrid Spain
- Department of Medicine, Instituto Carlos III CIBERES, Universidad Autónoma de Madrid Madrid Spain
| | | | - Carsten Schmidt‐Weber
- Zentrums Allergie & Umwelt (ZAUM) Technische Universität und Helmholtz Zentrum München Germany
| | - Peter Schmid‐Grendelmeier
- Allergy Unit, Department of Dermatology University Hospital of Zurich Zurich Switzerland
- Christine‐Kühne Center for Allergy Research and Education CK‐CARE Davos Davos Switzerland
| | - Mohamed Shamji
- Allergy & Clinical Immunology, Inflammation, Repair and Development, Imperial College, National Heart and Lung Institute Immunomodulation and Tolerance Group London UK
- Asthma UK Centre in Allergic Mechanisms of Asthma London UK
| | - Isabel Skypala
- Royal Brompton & Harefield NHS Foundation Trust London UK
- Imperial College London UK
| | | | - Otto Spranger
- Global Allergy and Asthma Patient Platform Vienna Austria
| | - Maria Torres
- Allergy Unit IBIMA, Regional University Hospital of Malaga, UMA Malaga Spain
- ARADyAL Network RD16/0006/0001, Carlos III Health Institute Madrid Spain
| | | | - Sergio Bonini
- Institute of Translational Pharmacology Italian National Research Council Rome Italy
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Novel vaccines targeting dendritic cells by coupling allergoids to mannan. ALLERGO JOURNAL 2018. [DOI: 10.1007/s15007-018-1764-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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Benito-Villalvilla C, Soria I, Subiza JL, Palomares O. Novel vaccines targeting dendritic cells by coupling allergoids to mannan. ACTA ACUST UNITED AC 2018; 27:256-262. [PMID: 30546997 PMCID: PMC6267119 DOI: 10.1007/s40629-018-0069-8] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Accepted: 04/09/2018] [Indexed: 01/27/2023]
Abstract
Allergen-specific immunotherapy (AIT) is the single disease-modifying treatment for allergy. Clinical trials show AIT to be safe and effective for many patients; however, it still faces problems related to efficacy, safety, long treatment duration and low patient adherence. There has been intensive research to develop alternative strategies, including novel administration routes, adjuvants or hypoallergenic molecules. Promising results are reported for some of them, but clinical progress is still moderate. Allergoids conjugated to nonoxidized mannan from Saccharomyces cerevisiae have emerged as a novel concept of vaccine targeting dendritic cells (DCs). Preclinical human and animal models demonstrated that allergoids conjugated to mannan enhance allergen uptake, promote healthy responses to allergens by inducing Th1 and T regulatory (Treg) cells, and show clinical efficacy in veterinary medicine. Dose-finding phase II clinical trials in humans are currently ongoing. We review the current stage of allergoids conjugated to mannan as next generation vaccines for AIT.
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Affiliation(s)
- Cristina Benito-Villalvilla
- 1Department of Biochemistry and Molecular Biology, School of Chemistry, Complutense University of Madrid, 28040 Madrid, Spain
| | | | | | - Oscar Palomares
- 1Department of Biochemistry and Molecular Biology, School of Chemistry, Complutense University of Madrid, 28040 Madrid, Spain
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Palomares O, Akdis M, Martín-Fontecha M, Akdis CA. Mechanisms of immune regulation in allergic diseases: the role of regulatory T and B cells. Immunol Rev 2017; 278:219-236. [DOI: 10.1111/imr.12555] [Citation(s) in RCA: 170] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Oscar Palomares
- Department of Biochemistry and Molecular Biology; School of Chemistry; Complutense University of Madrid; Madrid Spain
| | - Mübeccel Akdis
- Swiss Institute of Allergy and Asthma Research (SIAF); University of Zurich; Davos Switzerland
- Christine Kühne-Center for Allergy Research and Education (CK-CARE); Davos Switzerland
| | - Mar Martín-Fontecha
- Department of Organic Chemistry; School of Chemistry; Complutense University of Madrid; Madrid Spain
| | - Cezmi A. Akdis
- Swiss Institute of Allergy and Asthma Research (SIAF); University of Zurich; Davos Switzerland
- Christine Kühne-Center for Allergy Research and Education (CK-CARE); Davos Switzerland
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Crameri R. Artificial human sera: a breakthrough? Allergy 2016; 71:1649-1651. [PMID: 27591103 DOI: 10.1111/all.13044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- R. Crameri
- Swiss Institute of Allergy and Asthma Research (SIAF); University of Zürich; Davos Switzerland
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Zellweger F, Eggel A. IgE-associated allergic disorders: recent advances in etiology, diagnosis, and treatment. Allergy 2016; 71:1652-1661. [PMID: 27709638 DOI: 10.1111/all.13059] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/30/2016] [Indexed: 12/11/2022]
Abstract
IgE-associated allergic diseases belong to the most common inflammatory conditions. Their clinical manifestation ranges from mild symptoms to life-threatening episodes. Often patients experience a reduction in physical and psychologic well-being and suffer from a decreased quality of life due to disease activity. The continuously rising number of people that are affected by an allergic condition indicates an urgent need for better diagnostics and more efficient treatment options. Recent progress in the understanding of pathophysiologic mechanisms underlying IgE-associated allergic disorders has led to the identification of novel therapeutic targets and the development of drug candidates that are currently under evaluation. In this review, we highlight studies and clinical trials, which have helped to gain further insight in the etiology of IgE-associated allergic conditions as well as advances in the development of diagnostic tools and therapeutic approaches recently published in Allergy (European Journal of Allergy and Clinical Immunology).
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Affiliation(s)
- F. Zellweger
- Department of Rheumatology, Immunology and Allergology; University Hospital Bern; Bern Switzerland
- Department of Clinical Research; University of Bern; Bern Switzerland
| | - A. Eggel
- Department of Rheumatology, Immunology and Allergology; University Hospital Bern; Bern Switzerland
- Department of Clinical Research; University of Bern; Bern Switzerland
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Angelina A, Sirvent S, Palladino C, Vereda A, Cuesta-Herranz J, Eiwegger T, Rodríguez R, Breiteneder H, Villalba M, Palomares O. The lipid interaction capacity of Sin a 2 and Ara h 1, major mustard and peanut allergens of the cupin superfamily, endorses allergenicity. Allergy 2016; 71:1284-94. [PMID: 26991432 DOI: 10.1111/all.12887] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/12/2016] [Indexed: 12/29/2022]
Abstract
BACKGROUND Sin a 2 (11S globulin) and Ara h 1 (7S globulin) are major allergens from yellow mustard seeds and peanut, respectively. The ability of these two allergens to interact with lipid components remains unknown. OBJECTIVE To study the capacity of Sin a 2 and Ara h 1 to interact with lipid components and the potential effects of such interaction in their allergenic capacity. METHODS Spectroscopic and SDS-PAGE binding assays of Sin a 2 and Ara h 1 with different phospholipid vesicles and gastrointestinal and endolysosomal digestions in the presence or absence of lipids were performed. The capacity of human monocyte-derived dendritic cells (hmoDCs) to capture food allergens in the presence or absence of lipids, the induced cytokine signature, and the effect of allergens and lipids to regulate TLR2-L-induced NF-kB/AP-1 activation in THP1 cells were analyzed. RESULTS Sin a 2 and Ara h 1 bind phosphatidylglycerol (PG) acid but not phosphatidylcholine (PC) vesicles in a pH-dependent manner. The interaction of these two allergens with lipid components confers resistance to gastrointestinal digestion, reduces their uptake by hmoDCs, and enhances their stability to microsomal degradation. Mustard and peanut lipids favor a proinflammatory environment by increasing the IL-4/IL-10 ratio and IL-1β production by hmoDCs. The presence of mustard lipids and PG vesicles inhibits TLR2-L-induced NF-kB/AP-1 activation in THP1 cells. CONCLUSION Sin a 2 and Ara h 1 interact with lipid components, which might well contribute to explain the potent allergenic capacity of these two clinically relevant allergens belonging to the cupin superfamily.
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Affiliation(s)
- A. Angelina
- Department of Biochemistry and Molecular Biology; School of Chemistry; Complutense University of Madrid; Madrid Spain
| | - S. Sirvent
- Department of Biochemistry and Molecular Biology; School of Chemistry; Complutense University of Madrid; Madrid Spain
| | - C. Palladino
- Department of Pathophysiology and Allergy Research; Medical University of Vienna; Vienna Austria
| | - A. Vereda
- Servicio de Alergia; Fundación Jiménez Diaz; Madrid Spain
| | | | - T. Eiwegger
- Department of Paediatrics and Adolescent Medicine; Medical University of Vienna; Vienna Austria
- Division of Immunology and Allergy; Food allergy and Anaphylaxis Program; The Department of Paediatrics; Hospital for Sick Children; The University of Toronto; Toronto ON Canada
| | - R. Rodríguez
- Department of Biochemistry and Molecular Biology; School of Chemistry; Complutense University of Madrid; Madrid Spain
| | - H. Breiteneder
- Department of Pathophysiology and Allergy Research; Medical University of Vienna; Vienna Austria
| | - M. Villalba
- Department of Biochemistry and Molecular Biology; School of Chemistry; Complutense University of Madrid; Madrid Spain
| | - O. Palomares
- Department of Biochemistry and Molecular Biology; School of Chemistry; Complutense University of Madrid; Madrid Spain
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Zhu L, She T, Zhang Y, Li S, Xu Z, Yan J, Li H. Identification and characterization of ovary development-related protein EJO1 (Eri s 2) from the ovary of Eriocheir sinensis as a new food allergen. Mol Nutr Food Res 2016; 60:2275-2287. [PMID: 27240706 DOI: 10.1002/mnfr.201600144] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2016] [Revised: 04/26/2016] [Accepted: 05/19/2016] [Indexed: 11/06/2022]
Abstract
SCOPE Crab is a major source of shellfish allergens. Most studies have focused on allergens in crab muscle (CM) rather than on allergens in crab ovary (CO). This study aimed to identify potential allergens in CO from Eriocheir sinensis. METHODS AND RESULTS Dot blot and immunoblotting results revealed the differential reactivity of CM and CO extracts to positive sera from patients allergic to crabs. Four CO proteins showed good specific IgE-binding activities in 2-DE/immunoblotting analysis; mass spectrometry identified the proteins as hemocyanin, vitellogenin, ovary development-related protein EJO1and EJO2. The recently identified allergen EJO1 is named 'Eri s 2' in the World Health Organization and International Union of Immunological Societies (WHO/IUIS) allergen nomenclature database. Recombinant Eri s 2 exhibited good reactivity to positive sera, and pre-incubation with recombinant Eri s 2 abrogated the reactivity of positive sera from two patients to CO in a dose-dependent manner. Moreover, co-incubation of recombinant Eri s 2 with patient basophils dose-dependently promoted basophil activation, confirming the biological activity of Eri s 2. CONCLUSION CO tissue is an important allergen source, and Eri s 2 is a new crab allergen. This study provides insights that will be useful for component-resolved diagnostics for crab allergy.
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Affiliation(s)
- Lina Zhu
- School of Medical Laboratory, Tianjin Medical University, Tianjin, China
| | - Tiantian She
- School of Medical Laboratory, Tianjin Medical University, Tianjin, China
| | - Yingying Zhang
- School of Medical Laboratory, Tianjin Medical University, Tianjin, China
| | - Shaoshen Li
- Department of Medical Laboratory, Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital, Tianjin, China
| | - Zixian Xu
- Department of Medical Laboratory, Tianjin Chest Hospital, Tianjin, China
| | - Juanjuan Yan
- School of Medical Laboratory, Tianjin Medical University, Tianjin, China
| | - Huiqiang Li
- School of Medical Laboratory, Tianjin Medical University, Tianjin, China.
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Zhang Y, Zhu L, Li S, Zhang J, She T, Yan J, Bian Y, Li H. Identification of the major allergenic epitopes of Eriocheir sinensis roe hemocyanin: A novel tool for food allergy diagnoses. Mol Immunol 2016; 74:125-32. [DOI: 10.1016/j.molimm.2016.05.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2016] [Revised: 04/25/2016] [Accepted: 05/04/2016] [Indexed: 10/21/2022]
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Abstract
Food allergies are a global health issue with increasing prevalence. Allergic reactions can range from mild local symptoms to severe anaphylactic reactions. Significant progress has been made in diagnostic tools such as component-resolved diagnostics and its impact on risk stratification as well as in therapeutic approaches including biologicals. However, a cure for food allergy has not yet been achieved and patients and their families are forced to alter eating habits and social engagements, impacting their quality of life. New technologies and improved in vitro and in vivo models will advance our knowledge of the pathogenesis of food allergies and multicenter-multinational cohort studies will elucidate interactions between genetic background, lifestyle, and environmental factors. This review focuses on new insights and developments in the field of food allergy and summarizes recently published articles.
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Affiliation(s)
- A. Carrard
- Division of Pediatric Pulmonology and Allergology; University Children's Hospital, Inselspital; University of Bern; Bern Switzerland
| | - D. Rizzuti
- Division of Pediatric Gastroenterology, Hepatology and Nutrition; University Children's Hospital, Inselspital; University of Bern; Bern Switzerland
| | - C. Sokollik
- Division of Pediatric Gastroenterology, Hepatology and Nutrition; University Children's Hospital, Inselspital; University of Bern; Bern Switzerland
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