Publications by authors named "Mohamed H Shamji"

77 Publications

The role of mobile health technologies in stratifying patients for AIT and its cessation. The ARIA-EAACI perspective.

J Allergy Clin Immunol Pract 2021 Mar 1. Epub 2021 Mar 1.

Charité, Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Comprehensive Allergy Center, Department of Dermatology and Allergy, Berlin, Germany.

Allergen immunotherapy (AIT) is a proven therapeutic option for the treatment of allergic rhinitis and/or asthma. Many international or national practice guidelines have been produced, but the evidence-based method varies and they do not usually propose care pathways. The present paper considers the possible role of mHealth in AIT for allergic rhinitis/asthma. There are no currently available validated biologic biomarkers that can predict AIT success, and mHealth biomarkers have some relevance. In the current paper, the following aspects will be discussed: patient stratification for AIT, symptom medication scores for the follow-up of patients, clinical trials as well as the approach of the European Academy of Allergy and Clinical Immunology.
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http://dx.doi.org/10.1016/j.jaip.2021.02.035DOI Listing
March 2021

Passive Prophylactic Administration with a Single Dose of Anti-Fel d 1 Monoclonal Antibodies REGN1908-1909 in Cat Allergen-Induced Allergic Rhinitis: A Randomized, Double-blind, Placebo Controlled Trial.

Am J Respir Crit Care Med 2021 Mar 2. Epub 2021 Mar 2.

Regeneron Pharmaceuticals Inc, 7845, Tarrytown, New York, United States.

Rationale: Sensitization to Felis domesticus allergen 1 (Fel d 1) contributes to persistent allergic rhinitis and asthma. Existing treatment options for cat allergy, including allergen immunotherapy (AIT) are only moderately effective, and AIT has limited use due to safety concerns.

Objectives: To explore the relationship among the pharmaokinteic, clinical, and immunological effects of REGN1908-1909 (anti-Fel d 1 monoclonal antibodies) in patients after treatment.

Methods: Patients received REGN1908-1909 (n=36) or placebo (n=37) in a phase 1b study. Fel d 1-induced basophil and IgE-facilitated allergen binding responses were evaluated at baseline and days 8, 29 and 85. Cytokine and chemokine levels in nasal fluids were measured. REGN1908-1909 inhibition of allergen-IgE binding in patient serum was evaluated.

Measurements And Main Results: Peak serum drug concentrations were concordant with maximal observed clinical response. The anti-Fel d 1 IgE/cat-dander IgE ratio in pretreatment serum correlated with Total Nasal Symptom Score improvement. The allergen neutralizing capacity of REGN1908-1909 was observed in serum and nasal fluid, and was detected in an inhibition assay. Type-2 cytokines (IL-4, IL-5 and IL-13) and chemokines (CCL17/TARC, CCL5/RANTES) in nasal fluid were inhibited in REGN1908-1909-treated patients compared to placebo (all P < 0.05); IL-13 and IL-5 levels correlated with TNSS improvement. Ex vivo assays demonstrated that REGN1908 and REGN1909 combined was more potent than each alone for inhibiting FcεRI- and FcεRII (CD23)-mediated allergic responses and subsequent T-cell activation.

Conclusion: Single passive dose administration of Fel d 1-neutralizing IgG antibodies improved nasal symptoms in cat-allergic patients, and was underscored by suppression of FcεRI-, FcεRII- and Th2-mediated allergic responses. Clinical trial registration available at www.clinicaltrials.gov, ID: NCT02127801.
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http://dx.doi.org/10.1164/rccm.202011-4107OCDOI Listing
March 2021

What does climate change mean for people with pollen allergy?

Clin Exp Allergy 2021 Feb;51(2):202-205

National Heart and Lung Institute, Wright Fleming Institute, Imperial College London, London, UK.

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http://dx.doi.org/10.1111/cea.13826DOI Listing
February 2021

Innate Lymphoid Cells: The Missing Part Of A Puzzle In Food Allergy.

Allergy 2021 Feb 14. Epub 2021 Feb 14.

Immunomodulation and Tolerance group, Allergy and Clinical Immunology, Inflammation, Repair and Development, Imperial College London, London, United Kingdom.

Food allergy is an increasingly prevalent disease which is mainly driven by uncontrolled type 2 immune response. Currently, knowledge about the underlying mechanisms that initiate and promote the immune response to dietary allergens is limited. Patients with food allergy are commonly sensitized through the skin in their early life, later on developing allergy symptoms within the gastrointestinal tract. Food allergy results from a dysregulated type 2 response to food allergens, characterized by enhanced levels of IgE, IL-4, IL-5 and IL-13 with infiltration of mast cells, eosinophils and basophils. Recent studies raised a possible role for the involvement of innate lymphoid cells (ILCs) in driving food allergy. They represent a group of lymphocytes that lack specific, recombined antigen receptors. ILCs contribute to immune responses not only by releasing cytokines and other mediators but also by responding to cytokines produced by activated cells in their local microenvironment. Due to their localization at barrier surfaces ofthe airways, gut and skin, ILCs form a link between the innate and adaptive immunity. This review summarizes recent evidence on how skin and gastrointestinal mucosal immune system contribute to both homeostasis and the development of food allergy, as well as the involvement of ILCs towards inflammatory processes and regulatory mechanisms.
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http://dx.doi.org/10.1111/all.14776DOI Listing
February 2021

EAACI statement on the diagnosis, management and prevention of severe allergic reactions to COVID-19 vaccines.

Allergy 2021 Jan 16. Epub 2021 Jan 16.

Immunomodulation and Tolerance Group, Allergy and Clinical Immunology, Inflammation, Repair and Development, National Heart and Lung Institute, Imperial College London. Asthma UK Centre in Allergic Mechanisms of Asthma, London, United Kingdom.

The first approved COVID-19 vaccines include Pfizer/BioNTech BNT162B2, Moderna mRNA-1273 and AstraZeneca recombinant adenoviral ChAdOx1-S. Soon after approval, severe allergic reactions to the mRNA-based vaccines that resolved after treatment were reported. Regulatory agencies from the European Union, Unites States and the United Kingdom agree that vaccinations are contraindicated only when there is an allergy to one of the vaccine components or if there was a severe allergic reaction to the first dose. This position paper of the European Academy of Allergy and Clinical Immunology (EAACI) agrees with these recommendations and clarifies that there is no contraindication to administer these vaccines to allergic patients who do not have a history of an allergic reaction to any of the vaccine components. Importantly, as is the case for any medication, anaphylaxis may occur after vaccination in the absence of a history of allergic disease. Therefore, we provide a simplified algorithm of prevention, diagnosis and treatment of severe allergic reactions and a list of recommended medications and equipment for vaccine centres. We also describe potentially allergenic/immunogenic components of the approved vaccines and propose a workup to identify the responsible allergen. Close collaboration between academia, regulatory agencies and vaccine producers will facilitate approaches for patients at risks, such as incremental dosing of the second injection or desensitisation. Finally, we identify unmet research needs and propose a concerted international roadmap towards precision diagnosis and management to minimise the risk of allergic reactions to COVID-19 vaccines and to facilitate their broader and safer use.
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http://dx.doi.org/10.1111/all.14739DOI Listing
January 2021

Induction of IL-10-producing type 2 innate lymphoid cells by allergen immunotherapy is associated with clinical response.

Immunity 2021 Feb 14;54(2):291-307.e7. Epub 2021 Jan 14.

Immunomodulation and Tolerance Group, Allergy and Clinical Immunology, Department of National Heart and Lung Institute, Imperial College London, London, UK; NIHR Biomedical Research Centre, Asthma UK Centre in Allergic Mechanisms of Asthma, London, Imperial College London, London, UK. Electronic address:

The role of innate immune cells in allergen immunotherapy that confers immune tolerance to the sensitizing allergen is unclear. Here, we report a role of interleukin-10-producing type 2 innate lymphoid cells (IL-10 ILC2s) in modulating grass-pollen allergy. We demonstrate that KLRG1 but not KLRG1 ILC2 produced IL-10 upon activation with IL-33 and retinoic acid. These cells attenuated Th responses and maintained epithelial cell integrity. IL-10 KLRG1 ILC2s were lower in patients with grass-pollen allergy when compared to healthy subjects. In a prospective, double-blind, placebo-controlled trial, we demonstrated that the competence of ILC2 to produce IL-10 was restored in patients who received grass-pollen sublingual immunotherapy. The underpinning mechanisms were associated with the modification of retinol metabolic pathway, cytokine-cytokine receptor interaction, and JAK-STAT signaling pathways in the ILCs. Altogether, our findings underscore the contribution of IL-10 ILC2s in the disease-modifying effect by allergen immunotherapy.
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http://dx.doi.org/10.1016/j.immuni.2020.12.013DOI Listing
February 2021

Allergy prevention.

Clin Exp Allergy 2021 Jan;51(1):4-5

National Heart and Lung Institute, Wright Fleming Institute, Imperial College London, London, UK.

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http://dx.doi.org/10.1111/cea.13804DOI Listing
January 2021

ARIA-EAACI statement on severe allergic reactions to COVID-19 vaccines - an EAACI-ARIA position paper.

Allergy 2020 Dec 30. Epub 2020 Dec 30.

Charité Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Comprehensive Allergy Center, Department of Dermatology and Allergy, Berlin, Germany.

Coronavirus disease 2019 (COVID-19) vaccine BNT162b2 received approval and within the first few days of public vaccination several severe anaphylaxis cases occurred. An investigation is taking place to understand the cases and their triggers. The vaccine will be administered to a large number of individuals worldwide and concerns raised for severe adverse events might occur. With the current information, the European Academy of Allergy and Clinical Immunology (EAACI) states its position for the following preliminary recommendations that are to be revised as soon as more data emerges. To minimize the risk of severe allergic reactions in vaccinated individuals, it is urgently required to understand the specific nature of the reported severe allergic reactions, including the background medical history of the individuals affected and the mechanisms involved. To achieve this goal all clinical and laboratory information should be collected and reported. Mild and moderate allergic patients should not be excluded from the vaccine as the exclusion of all these patients from vaccination may have a significant impact on reaching the goal of population immunity. Health care practitioners vaccinating against COVID-19 are required to be sufficiently prepared to recognise and treat anaphylaxis properly with the ability to administer adrenaline. A mandatory observation period after vaccine administration of at least 15 minutes for all individuals should be followed. The current data has not shown any higher risk for patients suffering from allergic rhinitis or asthma and this message should be clearly stated by physicians to give our patients trust. The benefit of the vaccination clearly outweighs the risk of severe COVID-19 development including the more than 30% of the population suffering from allergic diseases.
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http://dx.doi.org/10.1111/all.14726DOI Listing
December 2020

Mechanisms of Allergen Immunotherapy in Allergic Rhinitis.

Curr Allergy Asthma Rep 2020 Dec 12;21(1). Epub 2020 Dec 12.

Immunomodulation and Tolerance Group, Allergy & Clinical Immunology, Inflammation, Repair and Development, National Heart & Lung Institute, Imperial College London, 1st Floor, Room 111, Sir Alexander Fleming Building, South Kensington Campus, London, SW7 2AZ, UK.

Purpose Of Review: Allergic rhinitis (AR) is a chronic inflammatory immunoglobulin (Ig) E-mediated disease of the nasal mucosa that can be triggered by the inhalation of seasonal or perennial allergens. Typical symptoms include sneezing, rhinorrhea, nasal itching, nasal congestion and symptoms of allergic conjunctivitis. AR affects a quarter of the population in the United States of America and Europe.

Recent Findings: AR has been shown to reduce work productivity in 36-59% of the patients with 20% reporting deteriorated job attendance. Moreover, 42% of children with AR report reduced at-school productivity and lower grades. Most importantly, AR impacts the patient's quality of life, due to sleep deprivation. However, a proportion of patients fails to respond to conventional medication and opts for the allergen immunotherapy (AIT), which currently is the only disease-modifying therapeutic option. AIT can be administered by either subcutaneous (SCIT) or sublingual (SLIT) route. Both routes of administration are safe, effective, and can lead to tolerance lasting years after treatment cessation. Both innate and adaptive immune responses that contribute to allergic inflammation are suppressed by AIT. Innate responses are ameliorated by reducing local mast cell, basophil, eosinophil, and circulating group 2 innate lymphoid cell frequencies which is accompanied by decreased basophil sensitivity. Induction of allergen-specific blocking antibodies, immunosuppressive cytokines, and regulatory T and B cell phenotypes are key pro-tolerogenic adaptive immune responses.

Conclusion: A comprehensive understanding of these mechanisms is necessary for optimal selection of AIT-responsive patients and monitoring treatment efficacy. Moreover, it could inspire novel and more efficient AIT approaches.
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http://dx.doi.org/10.1007/s11882-020-00977-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733588PMC
December 2020

Toll-Like Receptor Agonists as Adjuvants for Allergen Immunotherapy.

Front Immunol 2020 12;11:599083. Epub 2020 Nov 12.

Immunomodulation and Tolerance Group, Allergy and Clinical Immunology, Inflammation, Repair and Development, National Heart and Lung Institute, Imperial College London, London, United Kingdom.

Toll-like receptors (TLRs) are essential components of innate immunity and provide defensive inflammatory responses to invading pathogens. Located within the plasma membranes of cells and also intracellular endosomes, TLRs can detect a range of pathogen associated molecular patterns from bacteria, viruses and fungi. TLR activation on dendritic cells can propagate to an adaptive immune response, making them attractive targets for the development of both prophylactic and therapeutic vaccines. In contrast to conventional adjuvants such as aluminium salts, TLR agonists have a clear immunomodulatory profile that favours anti-allergic T lymphocyte responses. Consequently, the potential use of TLRs as adjuvants in Allergen Immunotherapy (AIT) for allergic rhinitis and asthma remains of great interest. Allergic Rhinitis is a Th2-driven, IgE-mediated disease that occurs in atopic individuals in response to exposure to otherwise harmless aeroallergens such as pollens, house dust mite and animal dander. AIT is indicated in subjects with allergic rhinitis whose symptoms are inadequately controlled by antihistamines and nasal corticosteroids. Unlike anti-allergic drugs, AIT is disease-modifying and may induce long-term disease remission through mechanisms involving upregulation of IgG and IgG4 antibodies, induction of regulatory T and B cells, and immune deviation in favour of Th1 responses that are maintained after treatment discontinuation. This process takes up to three years however, highlighting an unmet need for a more efficacious therapy with faster onset. Agonists targeting different TLRs to treat allergy are at different stages of development. Synthetic TLR4, and TLR9 agonists have progressed to clinical trials, while TLR2, TLR5 and TLR7 agonists been shown to have potent anti-allergic effects in human experiments and in animal studies. The anti-allergic properties of TLRs are broadly characterised by a combination of enhanced Th1 deviation, regulatory responses, and induction of blocking antibodies. While promising, a durable effect in larger clinical trials is yet to be observed and further long-term studies and comparative trials with conventional AIT are required before TLR adjuvants can be considered for inclusion in AIT. Here we critically evaluate experimental and clinical studies investigating TLRs and discuss their potential role in the future of AIT.
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http://dx.doi.org/10.3389/fimmu.2020.599083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688745PMC
November 2020

Altered chromatin landscape in circulating T follicular helper and regulatory cells following grass pollen subcutaneous and sublingual immunotherapy.

J Allergy Clin Immunol 2021 Feb 6;147(2):663-676. Epub 2020 Nov 6.

Immunomodulation and Tolerance Group, Allergy and Clinical Immunology, Department of National Heart and Lung Institute, London, United Kingdom; Asthma UK Centre in Allergic Mechanisms of Asthma, London, Imperial College London, London, United Kingdom. Electronic address:

Background: Allergen-specific immunotherapy is a disease-modifying treatment that induces long-term T-cell tolerance.

Objective: We sought to evaluate the role of circulating CXCR5PD-1 T follicular helper (cT) and T follicular regulatory (T) cells following grass pollen subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) and the accompanying changes in their chromatin landscape.

Methods: Phenotype and function of cT cells were initially evaluated in the grass pollen-allergic (GPA) group (n = 28) and nonatopic healthy controls (NAC, n = 13) by mathematical algorithms developed to manage high-dimensional data and cell culture, respectively. cT and T cells were further enumerated in NAC (n = 12), GPA (n = 14), SCIT- (n = 10), and SLIT- (n = 8) treated groups. Chromatin accessibility in cT and T cells was assessed by assay for transposase-accessible chromatin sequencing (ATAC-seq) to investigate epigenetic mechanisms underlying the differences between NAC, GPA, SCIT, and SLIT groups.

Results: cT cells were shown to be distinct from T2- and T2A-cell subsets, capable of secreting IL-4 and IL-21. Both cytokines synergistically promoted B-cell class switching to IgE and plasma cell differentiation. Grass pollen allergen induced cT-cell proliferation in the GPA group but not in the NAC group (P < .05). cT cells were higher in the GPA group compared with the NAC group and were lower in the SCIT and SLIT groups (P < .01). Time-dependent induction of IL-4, IL-21, and IL-6 was observed in nasal mucosa following intranasal allergen challenge in the GPA group but not in SCIT and SLIT groups. T and IL-10 cT cells were induced in SCIT and SLIT groups (all, P < .01). ATAC-seq analyses revealed differentially accessible chromatin regions in all groups.

Conclusions: For the first time, we showed dysregulation of cT cells in the GPA group compared to NAC, SCIT, and SLIT groups and induction of T and IL-10 cT cells following SCIT and SLIT. Changes in the chromatin landscape were observed following allergen-specific immunotherapy in cT and T cells.
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http://dx.doi.org/10.1016/j.jaci.2020.10.035DOI Listing
February 2021

Uncovering the immunological properties of isolated lymphoid follicles.

Allergy 2020 Sep 23. Epub 2020 Sep 23.

Immunomodulation and Tolerance Group, Allergy and Clinical Immunology, National Heart and Lung Institute, Imperial College London, London, UK.

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http://dx.doi.org/10.1111/all.14598DOI Listing
September 2020

Basophil Activation Test : A diagnostic, predictive and monitoring assay for Allergen Immunotherapy.

Allergy 2020 Sep 9. Epub 2020 Sep 9.

National Heart and Lung Institute, Imperial College London, London, United Kingdom.

For decades, the approach to clinical care has involved the assessment of a fairly small set of patients' signs and symptoms, sampled over a short period of time with limited attention given to individual variations in aetiology and pathophysiology. Subsequently, a therapy is assigned predominantly with a "one shoe fits all" approach. Precision medicine approaches are now starting to change ways to test, treat and develop new therapies for allergic and immunological disorders. (Figure 1).
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http://dx.doi.org/10.1111/all.14585DOI Listing
September 2020

Cardiovascular changes during peanut-induced allergic reactions in human subjects.

J Allergy Clin Immunol 2021 Feb 21;147(2):633-642. Epub 2020 Jul 21.

Section of Inflammation, Repair and Development, National Heart & Lung Institute, Imperial College London, London, United Kingdom.

Background: Food allergy is the most common cause of anaphylaxis. Changes in posture during acute reactions can trigger fatal outcomes, but the impact of allergic reactions on the cardiovascular system in nonfatal reactions remains poorly understood.

Objective: Our aim was to systematically evaluate changes in cardiovascular function during acute allergic reactions to peanut.

Methods: Participants underwent double-blind placebo-controlled food challenge to peanut as part of a clinical trial. Changes in hemodynamic parameters (heart rate, stroke volume, blood pressure, and peripheral blood flow) and electrocardiogram findings during food challenges were assessed using noninvasive continuous monitoring.

Results: A total of 57 adults (median age 24 years [interquartile range = 20-29]), 53% of whom were female, participated; 22 (39%) had anaphylaxis. Acute reactions were associated with significant changes in stroke volume (mean decrease of 4.2% [95% CI = 0.8-7.6; P = .03]), heart rate (mean increase 11.6% [95% CI = 8.4-14.8; P < .0001]), and peripheral blood flow (mean increase 19.7% [95% CI = 10.8-28.6; P < .0001]), irrespective of reaction severity. These changes were reproduced at a subsequent repeat peanut challenge in 26 participants, and could be reversed with administration of intravenous fluids which resulted in faster resolution of abdominal symptoms.

Conclusions: In this first detailed human study of cardiovascular changes during food-induced allergic reactions, we found evidence for significant fluid redistribution, independent of reaction severity. This provides a sound rationale for optimizing venous return during significant allergic reactions to food. Finally, these data provide a new paradigm for understanding severity in anaphylaxis, in which poor outcomes may occur as a result of a failure in compensatory mechanisms.
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http://dx.doi.org/10.1016/j.jaci.2020.06.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7858218PMC
February 2021

Immunology of COVID-19: Mechanisms, clinical outcome, diagnostics, and perspectives-A report of the European Academy of Allergy and Clinical Immunology (EAACI).

Allergy 2020 10;75(10):2445-2476

Institute of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.

With the worldwide spread of the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) resulting in declaration of a pandemic by the World Health Organization (WHO) on March 11, 2020, the SARS-CoV-2-induced coronavirus disease-19 (COVID-19) has become one of the main challenges of our times. The high infection rate and the severe disease course led to major safety and social restriction measures worldwide. There is an urgent need of unbiased expert knowledge guiding the development of efficient treatment and prevention strategies. This report summarizes current immunological data on mechanisms associated with the SARS-CoV-2 infection and COVID-19 development and progression to the most severe forms. We characterize the differences between adequate innate and adaptive immune response in mild disease and the deep immune dysfunction in the severe multiorgan disease. The similarities of the human immune response to SARS-CoV-2 and the SARS-CoV and MERS-CoV are underlined. We also summarize known and potential SARS-CoV-2 receptors on epithelial barriers, immune cells, endothelium and clinically involved organs such as lung, gut, kidney, cardiovascular, and neuronal system. Finally, we discuss the known and potential mechanisms underlying the involvement of comorbidities, gender, and age in development of COVID-19. Consequently, we highlight the knowledge gaps and urgent research requirements to provide a quick roadmap for ongoing and needed COVID-19 studies.
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http://dx.doi.org/10.1111/all.14462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361752PMC
October 2020

Reply.

J Allergy Clin Immunol 2020 08 21;146(2):457-458. Epub 2020 May 21.

ALK-Abelló A/S, Hørsholm, Denmark. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2020.03.011DOI Listing
August 2020

EAACI Allergen Immunotherapy User's Guide.

Pediatr Allergy Immunol 2020 05;31 Suppl 25:1-101

Department of Paediatrics, Imperial College London, London, UK.

Allergen immunotherapy is a cornerstone in the treatment of allergic children. The clinical efficiency relies on a well-defined immunologic mechanism promoting regulatory T cells and downplaying the immune response induced by allergens. Clinical indications have been well documented for respiratory allergy in the presence of rhinitis and/or allergic asthma, to pollens and dust mites. Patients who have had an anaphylactic reaction to hymenoptera venom are also good candidates for allergen immunotherapy. Administration of allergen is currently mostly either by subcutaneous injections or by sublingual administration. Both methods have been extensively studied and have pros and cons. Specifically in children, the choice of the method of administration according to the patient's profile is important. Although allergen immunotherapy is widely used, there is a need for improvement. More particularly, biomarkers for prediction of the success of the treatments are needed. The strength and efficiency of the immune response may also be boosted by the use of better adjuvants. Finally, novel formulations might be more efficient and might improve the patient's adherence to the treatment. This user's guide reviews current knowledge and aims to provide clinical guidance to healthcare professionals taking care of children undergoing allergen immunotherapy.
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http://dx.doi.org/10.1111/pai.13189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317851PMC
May 2020

The emerging role of T follicular helper (T) cells in aging: Influence on the immune frailty.

Ageing Res Rev 2020 08 25;61:101071. Epub 2020 Apr 25.

Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy; Istituti Clinici Scientifici Maugeri SpA Società Benefit (ICS Maugeri SpA SB), Telese Terme, BN, Italy.

The world population is undergoing a rapid expansion of older adults. Aging is associated with numerous changes that affect all organs and systems, including every component of the immune system. Immunosenescence is a multifaceted process characterized by poor response to vaccine and higher incidence of bacterial and viral infections, cancer, cardiovascular and autoimmune diseases. Immunosenescence has been associated with chronic low-grade inflammation referred to as inflammaging, whose underlying mechanisms remain incompletely elucidated, including age-related changes affecting components of the innate and adaptive immune system. T follicular helper (T) cells, present in lymphoid organs and in peripheral blood, are specialized in providing cognate help to B cells and are required for the production of immunoglobulins. Several subsets of T cells have been identified in humans and mice and modifications in T cell phenotype and function progressively occur with age. Dysfunctional T cells play a role in cancer, autoimmune and cardiovascular diseases, all conditions particularly prevalent in elderly subjects. A specialized population of Treg cells, named T follicular regulatory (T) cells, present in lymphoid organs and in peripheral blood, exerts opposing roles to T cells in regulating immunity. Indeed, changes in T/T cell ratio constitute a relevant feature of aging. Herein we discuss the cellular and molecular changes in both T cells and T cells that occur in aging and recent findings suggesting that T cells and/or their subsets could be involved in atherosclerosis, cancer, and autoimmunity.
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http://dx.doi.org/10.1016/j.arr.2020.101071DOI Listing
August 2020

In-vivo diagnostic test allergens in Europe: A call to action and proposal for recovery plan-An EAACI position paper.

Allergy 2020 09;75(9):2161-2169

Allergy Section, Department of Internal Medicine, Hospital Valld'Hebron, Barcelona, Spain.

Diagnostic allergens are defined as medicinal products in the EU. Marketing authorization by national authorities is necessary; however, diagnostic allergens are not homogeneously regulated in different EU member states. Allergen manufacturers argue with increasing costs forcing them to continuously reduce the diagnostic allergen portfolios offered to allergists. In contrast, EAACI and national European Allergy Societies see the need for the availability of a wide range of high-quality diagnostic allergens for in vivo diagnosis of IgE-mediated allergies not only covering predominant but also less frequent allergen sources. In a recent EAACI task force survey, the current practice of allergy diagnosis was shown to rely on skin tests as first option in almost 2/3 of all types of allergic diseases and in 90% regarding respiratory allergies. With the need to ensure the availability of high-quality diagnostic allergens in the EU, an action plan has been set up by EAACI to analyse the current regulatory demands in EU member states and to define possible solutions stated in this document: (a) simplification of authorization for diagnostic allergens; (b) specific regulation of special types of diagnostic allergens; (c) new models beyond the current model of homologous groups; (d) simplification of pharmacovigilance reporting; (e) reduction of regulation fees for diagnostic allergens; (f) reimbursement for diagnostic allergens. Joining forces of allergists, manufacturers and authorities are of high importance to ensure remaining relevant allergens in the EU markets to facilitate a sustainable and comprehensive service for the diagnosis and treatment of allergic diseases.
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http://dx.doi.org/10.1111/all.14329DOI Listing
September 2020

Nasal allergen challenge and environmental exposure chamber challenge: A randomized trial comparing clinical and biological responses to cat allergen.

J Allergy Clin Immunol 2020 06 10;145(6):1585-1597. Epub 2020 Mar 10.

MRC and Asthma UK, Centre in Allergic Mechanisms of Asthma, London, United Kingdom; Immunomodulation and Tolerance Group, Allergy and Clinical Immunology, Section of Inflammation Repair and Development, National Heart and Lung Institute, Imperial College London, London, United Kingdom.

Background: The direct-instillation nasal allergen challenge (NAC) and the environmental exposure chamber (EEC) are 2 methods of conducting controlled allergen provocations. The clinical and biological comparability of these methods has not been thoroughly investigated.

Objective: We sought to compare clinical and immunologic responses to cat allergen in NAC versus EEC.

Methods: Twenty-four participants were randomized to receive either NAC followed by a 2-day challenge in an EEC or a 2-day challenge in an EEC followed by NAC. Challenges were separated by 28-day washout periods. We measured total nasal symptom scores, peak nasal inspiratory flow, nasal (0-8 hours) and serum cytokines, serum antibodies, peripheral blood antigen-specific T lymphocytes, and gene expression in nasal scrapings. The primary outcome was the total nasal symptom score area under the curve for the first 3 hours after allergen exposure in NAC or after initiation of exposure in EEC.

Results: Both challenges increased IL-5 and IL-13 in nasal fluids and serum and resulted in altered nasal cell expression of gene modules related to mucosal biology and transcriptional regulation. Changes in gene modules, more so than cytokine measurements, showed significant associations with total nasal symptom score and peak nasal inspiratory flow. Overall, EEC exposure generated larger responses and more early terminations compared with NAC. Although the 2 challenges did not correlate in symptom magnitude or temporality, striking correlations were observed in cytokine levels.

Conclusions: Although clinical outcomes of NAC and EEC were temporally different and nonequivalent in magnitude, immunologic responses were similar. Selection of a particular allergen challenge method should depend on considerations of study objectives and cost.
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http://dx.doi.org/10.1016/j.jaci.2020.02.024DOI Listing
June 2020

Is pollen-food syndrome a frequent comorbidity in adults with irritable bowel syndrome?

Allergy 2020 07 14;75(7):1780-1783. Epub 2020 Feb 14.

Department of Allergy and Clinical Immunology, Royal Brompton & Harefield NHS Foundation Trust, London, UK.

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http://dx.doi.org/10.1111/all.14209DOI Listing
July 2020

Allergen-specific IgG memory B cells are temporally linked to IgE memory responses.

J Allergy Clin Immunol 2020 07 27;146(1):180-191. Epub 2019 Dec 27.

ALK-Abelló A/S, Hørsholm, Denmark. Electronic address:

Background: IgE is the least abundant immunoglobulin and tightly regulated, and IgE-producing B cells are rare. The cellular origin and evolution of IgE responses are poorly understood.

Objective: The cellular and clonal origin of IgE memory responses following mucosal allergen exposure by sublingual immunotherapy (SLIT) were investigated.

Methods: In a randomized double-blind, placebo-controlled, time course SLIT study, PBMCs and nasal biopsy samples were collected from 40 adults with seasonal allergic rhinitis at baseline and at 4, 8, 16, 28, and 52 weeks. RNA was extracted from PBMCs, sorted B cells, and nasal biopsy samples for heavy chain variable gene repertoire sequencing. Moreover, mAbs were derived from single B-cell transcriptomes.

Results: Combining heavy chain variable gene repertoire sequencing and single-cell transcriptomics yielded direct evidence of a parallel boost of 2 clonally and functionally related B-cell subsets of short-lived IgE plasmablasts and IgG memory B cells. Mucosal grass pollen allergen exposure by SLIT resulted in highly diverse IgE and IgG repertoires. These were extensively mutated and appeared relatively stable as per heavy chain isotype, somatic hypermutations, and clonal composition. Single IgG memory B-cell and IgE preplasmablast transcriptomes encoded antibodies that were specific for major grass pollen allergens and able to elicit basophil activation at very low allergen concentrations.

Conclusion: For the first time, we have shown that on mucosal allergen exposure, human IgE memory resides in allergen-specific IgG memory B cells. These cells rapidly switch isotype, expand into short-lived IgE plasmablasts, and serve as a potential target for therapeutic intervention.
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http://dx.doi.org/10.1016/j.jaci.2019.11.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7860973PMC
July 2020

Perspectives in allergen immunotherapy: 2019 and beyond.

Allergy 2019 12;74 Suppl 108:3-25

Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Zurich, Switzerland.

The seventh "Future of the Allergists and Specific Immunotherapy (FASIT)" workshop held in 2019 provided a platform for global experts from academia, allergy clinics, regulatory authorities and industry to review current developments in the field of allergen immunotherapy (AIT). Key domains of the meeting included the following: (a) Biomarkers for AIT and allergic asthma; (b) visions for the future of AIT; (c) progress and data for AIT in asthma and the updates of GINA and EAACI Asthma Guidelines (separated for house dust mite SCIT, SLIT tablets and SLIT drops; patient populations) including a review of clinically relevant endpoints in AIT studies in asthma; (d) regulatory prerequisites such as the "Therapy Allergen Ordinance" in Germany; (e) optimization of trial design in AIT clinical research; (f) challenges planning and conducting phase III (field) studies and the future role of Allergen Exposure Chambers (AEC) in AIT product development from the regulatory point of view. We report a summary of panel discussions of all six domains and highlight unmet needs and possible solutions for the future.
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http://dx.doi.org/10.1111/all.14077DOI Listing
December 2019

Intralymphatic immunotherapy in pollen-allergic young adults with rhinoconjunctivitis and mild asthma: A randomized trial.

J Allergy Clin Immunol 2020 03 24;145(3):1005-1007.e7. Epub 2019 Nov 24.

Department of Medicine Solna, Division of Immunology and Allergy, Karolinska Institutet and University Hospital, Stockholm, Sweden. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2019.11.017DOI Listing
March 2020

Next-generation Allergic Rhinitis and Its Impact on Asthma (ARIA) guidelines for allergic rhinitis based on Grading of Recommendations Assessment, Development and Evaluation (GRADE) and real-world evidence.

Authors:
Jean Bousquet Holger J Schünemann Akdis Togias Claus Bachert Martina Erhola Peter W Hellings Ludger Klimek Oliver Pfaar Dana Wallace Ignacio Ansotegui Ioana Agache Anna Bedbrook Karl-Christian Bergmann Mike Bewick Philippe Bonniaud Sinthia Bosnic-Anticevich Isabelle Bossé Jacques Bouchard Louis-Philippe Boulet Jan Brozek Guy Brusselle Moises A Calderon Walter G Canonica Luis Caraballo Vicky Cardona Thomas Casale Lorenzo Cecchi Derek K Chu Elisio M Costa Alvaro A Cruz Wienczyslawa Czarlewski Gennaro D'Amato Philippe Devillier Mark Dykewicz Motohiro Ebisawa Jean-Louis Fauquert Wytske J Fokkens Joao A Fonseca Jean-François Fontaine Bilun Gemicioglu Roy Gerth van Wijk Tari Haahtela Susanne Halken Despo Ierodiakonou Tomohisa Iinuma Juan-Carlos Ivancevich Marek Jutel Igor Kaidashev Musa Khaitov Omer Kalayci Jorg Kleine Tebbe Marek L Kowalski Piotr Kuna Violeta Kvedariene Stefania La Grutta Désirée Larenas-Linnemann Susanne Lau Daniel Laune Lan Le Philipp Lieberman Karin C Lodrup Carlsen Olga Lourenço Gert Marien Pedro Carreiro-Martins Erik Melén Enrica Menditto Hugo Neffen Gregoire Mercier Ralph Mosgues Joaquim Mullol Antonella Muraro Leyla Namazova Ettore Novellino Robyn O'Hehir Yoshitaka Okamoto Ken Ohta Hae Sim Park Petr Panzner Giovanni Passalacqua Nhan Pham-Thi David Price Graham Roberts Nicolas Roche Christine Rolland Nelson Rosario Dermot Ryan Boleslaw Samolinski Mario Sanchez-Borges Glenis K Scadding Mohamed H Shamji Aziz Sheikh Ana-Maria Todo Bom Sanna Toppila-Salmi Ioana Tsiligianni Marylin Valentin-Rostan Arunas Valiulis Erkka Valovirta Maria-Teresa Ventura Samantha Walker Susan Waserman Arzu Yorgancioglu Torsten Zuberbier

J Allergy Clin Immunol 2020 01 15;145(1):70-80.e3. Epub 2019 Oct 15.

Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Uniersität zu Berlin and Berlin Institute of Health, Comprehensive Allergy-Centre, Department of Dermatology and Allergy, member of GA(2)LEN, Berlin, Germany.

The selection of pharmacotherapy for patients with allergic rhinitis aims to control the disease and depends on many factors. Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines have considerably improved the treatment of allergic rhinitis. However, there is an increasing trend toward use of real-world evidence to inform clinical practice, especially because randomized controlled trials are often limited with regard to the applicability of results. The Contre les Maladies Chroniques pour un Vieillissement Actif (MACVIA) algorithm has proposed an allergic rhinitis treatment by a consensus group. This simple algorithm can be used to step up or step down allergic rhinitis treatment. Next-generation guidelines for the pharmacologic treatment of allergic rhinitis were developed by using existing GRADE-based guidelines for the disease, real-world evidence provided by mobile technology, and additive studies (allergen chamber studies) to refine the MACVIA algorithm.
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http://dx.doi.org/10.1016/j.jaci.2019.06.049DOI Listing
January 2020

Mucosal IgE immune responses in respiratory diseases.

Curr Opin Pharmacol 2019 06 17;46:100-107. Epub 2019 Jun 17.

Immunomodulation and Tolerance Group, Allergy and Clinical Immunology, Inflammation, Repair and Development, National Heart and Lung Institute, Imperial College London, and the MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, London, United Kingdom. Electronic address:

IgE is the less abundant immunoglobulin isotype in serum and displays higher affinity for its cognate Fc receptor (FcεRI) than the rest of antibody isotypes. Moreover, the class switch recombination and the generation of memory responses remarkably differ between IgE and other isotypes. Importantly, class switch recombination to IgE can occur in the mucosae, preferentially through the sequential switching from IgG. Therefore, resident effector cells get rapidly sensitized, and free IgE can be found in mucosal secretions. All these aspects explain the involvement of IgE in respiratory diseases. In allergic rhinitis and allergic asthma, the IgE-sensitization to environmental allergens triggers an eosinophilic inflammation of the airway mucosa of atopic patients. In recent years, growing evidence indicates that some non-atopic patients with nasal reactivity to allergens display nasal eosinophilic inflammation, which could be triggered by the local production of allergen-specific IgE. This phenotype has been termed local allergic rhinitis. Mucosal IgE is also implicated in the pathophysiology of chronic rhinosinusitis with nasal polyps, even though the mechanisms for IgE synthesis might differ in this case. The role of IgE as mediator of airway diseases identify this marker as a therapeutic target. Some biologicals antagonize IgE-mediated inflammation of the airway mucosa, but they have not shown a beneficial long-term effect after discontinuation. In contrast, allergen immunotherapy does not only control the symptoms of airway allergy, but it also induces a long-lasting effect after discontinuation, thus modifying the natural course of the disease.
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http://dx.doi.org/10.1016/j.coph.2019.05.009DOI Listing
June 2019

Measurement of Allergen-Specific Inhibitory Antibody Activity.

Methods Mol Biol 2019 ;2020:33-43

Immune Targeting Systems (ITS) Ltd., London, UK.

Specific allergen immunotherapy (AIT) is an effective treatment for IgE-mediated allergic diseases and involves T- and B-cell-mediated events. IgE receptors on the surface of antigen-presenting cells facilitate the presentation of allergens in the presence of specific IgE antibody resulting in T-cell activation. Interference with these IgE-dependent mechanisms by "blocking" IgG antibodies suppresses pro-inflammatory Th2 cell responses and manifests as a reduction in allergic responses in vivo.In vitro assays used to measure the inhibition of binding of allergen-IgE complexes have previously utilized proliferation of antigen-specific T-cell clones as an assay readout. Here we describe two simplified assays to measure allergen binding without the complexity of generating T-cell clones. The IgE-facilitated allergen binding assay (IgE-FAB) utilizes flow cytometry to measure the binding of allergen-IgE complexes to EBV-transformed B cells. The enzyme-linked immunosorbent-facilitated antigen binding (ELIFAB) assay uses standard ELISA-based techniques to measure allergen-IgE binding to plate-bound CD23, the low-affinity IgE receptor expressed on B cells.
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http://dx.doi.org/10.1007/978-1-4939-9591-2_3DOI Listing
March 2020

2019 ARIA Care pathways for allergen immunotherapy.

Authors:
Jean Bousquet Oliver Pfaar Alkis Togias Holger J Schünemann Ignacio Ansotegui Nikolaos G Papadopoulos Ioanna Tsiligianni Ioana Agache Josep M Anto Claus Bachert Anna Bedbrook Karl-Christian Bergmann Sinthia Bosnic-Anticevich Isabelle Bosse Jan Brozek Moises A Calderon Giorgio W Canonica Luigi Caraballo Victoria Cardona Thomas Casale Lorenzo Cecchi Derek Chu Elisio Costa Alvaro A Cruz Wienczyslawa Czarlewski Stephen R Durham George Du Toit Mark Dykewicz Motohiro Ebisawa Jean Luc Fauquert Montserrat Fernandez-Rivas Wytske J Fokkens João Fonseca Jean-François Fontaine Roy Gerth van Wijk Tari Haahtela Susanne Halken Peter W Hellings Despo Ierodiakonou Tomohisa Iinuma Juan Carlos Ivancevich Lars Jacobsen Marek Jutel Igor Kaidashev Musa Khaitov Omer Kalayci Jörg Kleine Tebbe Ludger Klimek Marek L Kowalski Piotr Kuna Violeta Kvedariene Stefania La Grutta Désirée Larenas-Linemann Susanne Lau Daniel Laune Lan Le Karin Lodrup Carlsen Olga Lourenço Hans-Jørgen Malling Gert Marien Enrica Menditto Gregoire Mercier Joaquim Mullol Antonella Muraro Robyn O'Hehir Yoshitaka Okamoto Giovanni B Pajno Hae-Sim Park Petr Panzner Giovanni Passalacqua Nhan Pham-Thi Graham Roberts Ruby Pawankar Christine Rolland Nelson Rosario Dermot Ryan Bolesław Samolinski Mario Sanchez-Borges Glenis Scadding Mohamed H Shamji Aziz Sheikh Gunter J Sturm Ana Todo Bom Sanna Toppila-Salmi Maryline Valentin-Rostan Arunas Valiulis Erkka Valovirta Maria-Teresa Ventura Ulrich Wahn Samantha Walker Dana Wallace Susan Waserman Arzu Yorgancioglu Torsten Zuberbier

Allergy 2019 11 15;74(11):2087-2102. Epub 2019 Jul 15.

Department of Dermatology and Allergy, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Berlin Institute of Health, Comprehensive Allergy Centre, Member of GA2LEN, Humboldt-Uniersität zu Berlin, Berlin, Germany.

Allergen immunotherapy (AIT) is a proven therapeutic option for the treatment of allergic rhinitis and/or asthma. Many guidelines or national practice guidelines have been produced but the evidence-based method varies, many are complex and none propose care pathways. This paper reviews care pathways for AIT using strict criteria and provides simple recommendations that can be used by all stakeholders including healthcare professionals. The decision to prescribe AIT for the patient should be individualized and based on the relevance of the allergens, the persistence of symptoms despite appropriate medications according to guidelines as well as the availability of good-quality and efficacious extracts. Allergen extracts cannot be regarded as generics. Immunotherapy is selected by specialists for stratified patients. There are no currently available validated biomarkers that can predict AIT success. In adolescents and adults, AIT should be reserved for patients with moderate/severe rhinitis or for those with moderate asthma who, despite appropriate pharmacotherapy and adherence, continue to exhibit exacerbations that appear to be related to allergen exposure, except in some specific cases. Immunotherapy may be even more advantageous in patients with multimorbidity. In children, AIT may prevent asthma onset in patients with rhinitis. mHealth tools are promising for the stratification and follow-up of patients.
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http://dx.doi.org/10.1111/all.13805DOI Listing
November 2019