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      Transcriptome analysis and safety profile of the early-phase clinical response to an adjuvanted grass allergoid immunotherapy

      a , , a , a , b , a

      The World Allergy Organization Journal

      World Allergy Organization

      Grass pollen, Allergen immunotherapy, Allergoid, Safety, Transcriptome, ARC, adverse reaction complex, ADRs, adverse drug reactions, AE, adverse events, AIT, allergen mmunotherapy, DC, dendritic cell, EAACI, European Academy of Allergy and Clinical Immunology, FEV, forced expiratory volume, FVC, forced vital capacity, IPA, Ingenuity Pathway Analysis, MATA, modified allergen tyrosine adsorbate, MCT, microcrystalline tyrosine, MPL, monophosphoryl lipid A, mRNA, messenger ribosomal nucleic acid, SAEs, serious adverse events, SAR, seasonal allergic rhinoconjunctivitis, SD, standard deviation, SIT, specific immunotherapy, SU, standardized units, TEAEs, treatment-emergent adverse events, TLR, toll-like receptor, TSS, total symptom score, URA, Upstream Regulator Analysis

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          Abstract

          Background

          Specific immunotherapy is the only type of disease-modifying treatment, which induces rapid desensitization and long-term sustained unresponsiveness in patients with seasonal allergic rhinoconjunctivitis. The safety and tolerability of a new cumulative dose regimen of 35600 SU Grass MATA MPL for subcutaneous immunotherapy were assessed in pre-seasonal, single-blind, placebo controlled Phase I clinical study. Underlying immunological mechanisms were explored using transcriptome analysis of peripheral blood mononuclear cells.

          Methods

          Study subjects with a history of moderate to severe seasonal allergic rhinitis and/or conjunctivitis (SAR) due to grass ( Pooideae) pollen exposure were randomized on a 1:1 ratio to receive either six 1.0 mL injections of cumulative dose regimen 35600 SU of Grass MATA MPL or placebo. The study consisted of three periods: screening, randomization and treatment and End of Study period. Blood samples were taken for clinical safety laboratory assessments and for the assessment of gene expression analysis during screening visit and End of Study visit. The safety statistics was calculated using Fisher's exact test. Delta Delta Ct method analysis of RT 2 Profiler PCR Array gene expression results was used to calculate changes in gene expression level. Genes with the absolute value of log 2 fold change greater than ±1.1 and p-value less than 0.05 were identified as differentially expressed and underwent IPA data analysis.

          Results

          The results of the study indicated that the higher cumulative dose regimen of the immunotherapy was well-tolerated. Changes in gene expression profile were associated with early immune responses implicating innate and adaptive immune mechanisms. Pathways and mechanistic network analysis via IPA mapped differentially expressed genes onto canonical pathways related to T cell differentiation, cytokine signalling and Th1/Th2 activation pathways. The transcriptome findings of the study could be further verified in large-scale field studies in order to explore their potential as predictive markers of successful immunotherapy.

          Conclusions

          The higher dose cumulative regime 35600 SU of Grass MATA MPL vaccine was well tolerated and safe. Molecular markers IL-27, IL-10, IL-4, TNF, IFNγ, TGFβ and TLR4 were the main predicted molecular drivers of the observed gene expression changes following early stages of SIT with Grass MATA MPL immunotherapy.

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          Most cited references 35

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          Update on allergy immunotherapy: American Academy of Allergy, Asthma & Immunology/European Academy of Allergy and Clinical Immunology/PRACTALL consensus report.

          Allergy immunotherapy (AIT) is an effective treatment for allergic asthma and rhinitis, as well as venom-induced anaphylaxis. In addition to reducing symptoms, AIT can change the course of allergic disease and induce allergen-specific immune tolerance. In current clinical practice immunotherapy is delivered either subcutaneously or sublingually; some allergens, such as grass pollen, can be delivered through either route, whereas others, such as venoms, are only delivered subcutaneously. Both subcutaneous and sublingual immunotherapy appear to have a duration of efficacy of up to 12 years, and both can prevent the development of asthma and new allergen sensitivities. In spite of the advances with AIT, safer and more effective AIT strategies are needed, especially for patients with asthma, atopic dermatitis, or food allergy. Novel approaches to improve AIT include use of adjuvants or recombinant allergens and alternate routes of administration. As part of the PRACTALL initiatives, the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunology nominated an expert team to develop a comprehensive consensus report on the mechanisms of AIT and its use in clinical practice, as well as unmet needs and ongoing developments in AIT. This resulting report is endorsed by both academies. Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.
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            Optimal dose, efficacy, and safety of once-daily sublingual immunotherapy with a 5-grass pollen tablet for seasonal allergic rhinitis.

            Sublingual immunotherapy is well tolerated and data suggest its effectiveness for the treatment of allergic rhinitis in adults, but it lacks optimum dose definition. To assess the efficacy, safety, and optimal dose of grass pollen tablets for immunotherapy of patients with allergic rhinoconjunctivitis. In this multinational, randomized, double-blind, placebo-controlled study, 628 adults with grass pollen rhinoconjunctivitis (confirmed by positive skin prick test and serum-specific IgE) received 1 of 3 doses of a standardized 5-grass pollen extract, or placebo, administered sublingually using a once-daily tablet formulation. The treatment was initiated 4 months before the estimated pollen season and continued throughout the season. The primary outcome was Rhinoconjunctivitis Total Symptom Score; secondary outcomes included 6 individual symptom scores, rescue medication use, quality of life, and safety assessments. Both the 300-index of reactivity (IR) and 500-IR doses significantly reduced mean Rhinoconjunctivitis Total Symptom Score (3.58 +/- 3.0, P = .0001; and 3.74 +/- 3.1, P = .0006, respectively) compared with placebo (4.93 +/- 3.2) in the intent-to-treat and per-protocol analyses. The 100-IR group (4.70 +/- 3.1) score was not significantly different from placebo. Analysis of all secondary efficacy variables (sneezing, runny nose, itchy nose, nasal congestion, watery eyes, itchy eyes, rescue medication usage, and quality of life) confirmed the efficacy of the 300-IR and 500-IR doses. No serious side effects were reported. In the first pollen season, the efficacy and safety of sublingual immunotherapy with grass tablets was confirmed. The 300-IR and 500-IR doses both demonstrated significant efficacy compared with placebo. The risk-benefit ratio favors the use of 300-IR tablets for clinical practice.
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              Mechanisms of allergen-specific immunotherapy and immune tolerance to allergens

              Substantial progress in understanding mechanisms of immune regulation in allergy, asthma, autoimmune diseases, tumors, organ transplantation and chronic infections has led to a variety of targeted therapeutic approaches. Allergen-specific immunotherapy (AIT) has been used for 100 years as a desensitizing therapy for allergic diseases and represents the potentially curative and specific way of treatment. The mechanisms by which allergen-AIT has its mechanisms of action include the very early desensitization effects, modulation of T- and B-cell responses and related antibody isotypes as well as inhibition of migration of eosinophils, basophils and mast cells to tissues and release of their mediators. Regulatory T cells (Treg) have been identified as key regulators of immunological processes in peripheral tolerance to allergens. Skewing of allergen-specific effector T cells to a regulatory phenotype appears as a key event in the development of healthy immune response to allergens and successful outcome in AIT. Naturally occurring FoxP3+ CD4+CD25+ Treg cells and inducible type 1 Treg (Tr1) cells contribute to the control of allergen-specific immune responses in several major ways, which can be summarized as suppression of dendritic cells that support the generation of effector T cells; suppression of effector Th1, Th2 and Th17 cells; suppression of allergen-specific IgE, and induction of IgG4; suppression of mast cells, basophils and eosinophils and suppression of effector T cell migration to tissues. New strategies for immune intervention will likely include targeting of the molecular mechanisms of allergen tolerance and reciprocal regulation of effector and regulatory T cell subsets.
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                Author and article information

                Contributors
                Journal
                World Allergy Organ J
                World Allergy Organ J
                The World Allergy Organization Journal
                World Allergy Organization
                1939-4551
                16 November 2019
                November 2019
                16 November 2019
                : 12
                : 11
                Affiliations
                [a ]Allergy Therapeutics PLC (UK), Worthing, BN14 8SA, United Kingdom
                [b ]Faculty of Pharmaceutical Medicine, Royal Colleges of UK, 326a City Road, London, ECIV 2PT, United Kingdom
                Author notes
                []Corresponding author. Allergy Therapeutics PLC (UK), Worthing, BN14 8SA, United Kingdom. Sviatlana.Starchenka@ 123456allergytherapeutics.com
                Article
                S1939-4551(19)31243-8 100087
                10.1016/j.waojou.2019.100087
                6872854
                Crown Copyright © 2019 Published by Elsevier Inc. on behalf of World Allergy Organization.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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