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      Next-Generation of Allergen-Specific Immunotherapies: Molecular Approaches

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          Abstract

          Purpose of Review

          The aim of this article is to discuss how allergen-specific immunotherapy (AIT) can be improved through molecular approaches. We provide a summary of next-generation molecular AIT approaches and of their clinical evaluation. Furthermore, we discuss the potential of next generation molecular AIT forms for the treatment of severe manifestations of allergy and mention possible future molecular strategies for the secondary and primary prevention of allergy.

          Recent Findings

          AIT has important advantages over symptomatic forms of allergy treatment but its further development is limited by the quality of the therapeutic antigen preparations which are derived from natural allergen sources. The field of allergy diagnosis is currently undergoing a dramatic improvement through the use of molecular testing with defined, mainly recombinant allergens which allows high-resolution diagnosis. Several studies demonstrate that molecular testing in early childhood can predict the development of symptomatic allergy later on in life.

          Summary

          Clinical studies indicate that molecular AIT approaches have the potential to improve therapy of allergic diseases and may be used as allergen-specific forms of secondary and eventually primary prevention for allergy.

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          Most cited references110

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          Long-term clinical efficacy of grass-pollen immunotherapy.

          Pollen immunotherapy is effective in selected patients with IgE-mediated seasonal allergic rhinitis, although it is questionable whether there is long-term benefit after the discontinuation of treatment. We conducted a randomized, double-blind, placebo-controlled trial of the discontinuation of immunotherapy for grass-pollen allergy in patients in whom three to four years of this treatment had previously been shown to be effective. During the three years of this trial, primary outcome measures were scores for seasonal symptoms and the use of rescue medication. Objective measures included the immediate conjunctival response and the immediate and late skin responses to allergen challenge. Cutaneous-biopsy specimens obtained 24 hours after intradermal allergen challenge were examined for T-cell infiltration and the presence of cytokine-producing T helper cells (TH2 cells) (as evidenced by the presence of interleukin-4 messenger RNA). A matched group of patients with hay fever who had not received immunotherapy was followed as a control for the natural course of the disease. Scores for seasonal symptoms and the use of rescue antiallergic medication, which included short courses of prednisolone, remained low after the discontinuation of immunotherapy, and there was no significant difference between patients who continued immunotherapy and those who discontinued it. Symptom scores in both treatment groups (median areas under the curve in 1995, 921 for continuation of immunotherapy and 504 for discontinuation of immunotherapy; P=0.60) were markedly lower than those in the group that had not received immunotherapy (median value in 1995, 2863). Although there was a tendency for immediate sensitivity to allergen to return late after discontinuation, there was a sustained reduction in the late skin response and associated CD3+ T-cell infiltration and interleukin-4 messenger RNA expression. Immunotherapy for grass-pollen allergy for three to four years induces prolonged clinical remission accompanied by a persistent alteration in immunologic reactivity.
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            Specific immunotherapy has long-term preventive effect of seasonal and perennial asthma: 10-year follow-up on the PAT study.

            3-year subcutaneous specific immunotherapy (SIT) in children with seasonal allergic rhinoconjunctivitis reduced the risk of developing asthma during treatment and 2 years after discontinuation of SIT (5-year follow-up) indicating long-term preventive effect of SIT. We evaluated the long-term clinical effect and the preventive effect of developing asthma 7-years after termination of SIT. One hundred and forty-seven subjects, aged 16-25 years with grass and/or birch pollen allergy was investigated 10 years after initiation of a 3-year course of SIT with standardized allergen extracts of grass and/or birch or no SIT respectively. Conjunctival provocations were performed outside the season and methacholine bronchial provocations were performed during the season and winter. Asthma was assessed by clinical evaluation. The significant improvements in rhinoconjunctivitis and conjunctival sensitivity persisted at the 10-year follow-up. Significantly less actively treated subjects had developed asthma at 10-year follow-up as evaluated by clinical symptoms [odds ratio 2.5 (1.1-5.9)]. Patients who developed asthma among controls were 24/53 and in the SIT group 16/64. The longitudinal treatment effect when adjusted for bronchial hyper-responsiveness and asthma status at baseline including all observations at 3, 5 and 10 years follow-up (children with or without asthma at baseline, n = 189; 511 observations) was statistically significant (P = 0.0075). The odds ratio for no-asthma was 4.6 95% CI (1.5-13.7) in favor of SIT. A 3-year course of SIT with standardized allergen extracts has shown long-term clinical effects and the potential of preventing development of asthma in children with allergic rhinoconjunctivitis up to 7 years after treatment. Specific immunotherapy has long-term clinical effects and the potential of preventing development of asthma in children with allergic rhino conjunctivitis up to 7 years after treatment termination.
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              Immunological mechanisms of allergen-specific immunotherapy.

              Allergen-specific immunotherapy has been carried out for almost a century and remains one of the few antigen-specific treatments for inflammatory diseases. The mechanisms by which allergen-specific immunotherapy exerts its effects include the modulation of both T-cell and B-cell responses to allergen. There is a strong rationale for improving the efficacy of allergen-specific immunotherapy by reducing the incidence and severity of adverse reactions mediated by IgE. Approaches to address this problem include the use of modified allergens, novel adjuvants and alternative routes of administration. This article reviews the development of allergen-specific immunotherapy, our current understanding of its mechanisms of action and its future prospects.
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                Author and article information

                Contributors
                +43-1-40400-51080 , rudolf.valenta@meduniwien.ac.at
                Journal
                Curr Allergy Asthma Rep
                Curr Allergy Asthma Rep
                Current Allergy and Asthma Reports
                Springer US (New York )
                1529-7322
                1534-6315
                9 June 2018
                9 June 2018
                2018
                : 18
                : 7
                : 39
                Affiliations
                [1 ]ISNI 0000 0000 9259 8492, GRID grid.22937.3d, Division of Immunopathology, Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, , Medical University of Vienna, ; Waehringer Guertel 18-20, 1090 Vienna, Austria
                [2 ]GRID grid.465277.5, NRC Institute of Immunology FMBA of Russia, ; Moscow, Russia
                [3 ]ISNI 0000 0001 2288 8774, GRID grid.448878.f, Laboratory of Immunopathology, Department of Clinical Immunology and Allergy, , Sechenov First Moscow State Medical University, ; Moscow, Russia
                [4 ]Scientific Centre of Children’s Health, Moscow, Russia
                [5 ]International Network of Universities for Molecular Allergololgy and Immunology, Vienna, Austria
                Article
                790
                10.1007/s11882-018-0790-x
                5994214
                29886521
                815533ab-b627-4d39-9eab-391b46215bc4
                © The Author(s) 2018

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100002428, Austrian Science Fund;
                Award ID: F4605
                Award Recipient :
                Funded by: Biomay AG
                Funded by: Government of Russian Federation
                Award ID: 14.W03.31.0024
                Award Recipient :
                Categories
                Immunotherapy and Immunomodulators (B Vickery, Section Editor)
                Custom metadata
                © Springer Science+Business Media, LLC, part of Springer Nature 2018

                Immunology
                allergy,allergen,molecular allergology,allergen-specific immunotherapy (ait),recombinant allergen,hypoallergens,peptides,allergen-specific prevention of allergy,peptide-carrier vaccine

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