Publications
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Roth-Walter F, Adcock IM, Benito-Villalvilla C, et al., 2021, Immune modulation via T regulatory cell enhancement: disease-modifying therapies for autoimmunity and their potential for chronic allergic and inflammatory diseases - An EAACI position paper of the Task Force on Immunopharmacology (TIPCO)., Allergy, Vol: 76, Pages: 90-113, ISSN: 0105-4538
Therapeutic advances using targeted biologicals and small molecule drugs have achieved significant success in the treatment of chronic allergic, autoimmune and inflammatory diseases particularly for some patients with severe, treatment-resistant forms. This has been aided by improved identification of disease phenotypes. Despite these achievements, not all severe forms of chronic inflammatory and autoimmune diseases are successfully targeted, and current treatment options, besides allergen immunotherapy for selected allergic diseases, fail to change the disease course. T cell-based therapies aim to cure diseases through the selective induction of appropriate immune responses following the delivery of engineered, specific cytotoxic or regulatory T cells (Tregs). Adoptive cell therapies (ACT) with genetically engineered T cells have revolutionized the oncology field, bringing curative treatment for leukemia and lymphoma, while therapies exploiting the suppressive functions of Tregs have been developed in non-oncological settings, such as in transplantation and autoimmune diseases. ACT with Tregs are also being considered in non-oncological settings such as cardiovascular disease, obesity and chronic inflammatory disorders. After describing the general features of T cell-based approaches and current applications in autoimmune diseases, this position paper reviews the experimental models testing or supporting T cell-based approaches, especially Treg-based approaches, in severe IgE-mediated responses and chronic respiratory airway diseases, such as severe asthma and COPD. Along with an assessment of challenges and unmet needs facing the application of ACT in these settings, this article underscores the potential of ACT to offer curative options for patients with severe or treatment-resistant forms of these immune-driven disorders.
Kermani NZ, Saqi M, Agapow P, et al., 2021, Type 2-low asthma phenotypes by integration of sputum transcriptomics and serum proteomics., Allergy, Vol: 76, Pages: 380-383, ISSN: 0105-4538
Heaney LG, Busby J, Hanratty CE, et al., 2021, Composite type-2 biomarker strategy versus a symptom-risk-based algorithm to adjust corticosteroid dose in patients with severe asthma: a multicentre, single-blind, parallel group, randomised controlled trial, The Lancet Respiratory Medicine, Vol: 9, Pages: 57-68, ISSN: 2213-2600
BACKGROUND: Asthma treatment guidelines recommend increasing corticosteroid dose to control symptoms and reduce exacerbations. This approach is potentially flawed because symptomatic asthma can occur without corticosteroid responsive type-2 (T2)-driven eosinophilic inflammation, and inappropriately high-dose corticosteroid treatment might have little therapeutic benefit with increased risk of side-effects. We compared a biomarker strategy to adjust corticosteroid dose using a composite score of T2 biomarkers (fractional exhaled nitric oxide [FENO], blood eosinophils, and serum periostin) with a standardised symptom-risk-based algorithm (control). METHODS: We did a single-blind, parallel group, randomised controlled trial in adults (18-80 years of age) with severe asthma (at treatment steps 4 and 5 of the Global Initiative for Asthma) and FENO of less than 45 parts per billion at 12 specialist severe asthma centres across England, Scotland, and Northern Ireland. Patients were randomly assigned (4:1) to either the biomarker strategy group or the control group by an online electronic case-report form, in blocks of ten, stratified by asthma control and use of rescue systemic steroids in the previous year. Patients were masked to study group allocation throughout the entirety of the study. Patients attended clinic every 8 weeks, with treatment adjustment following automated treatment-group-specific algorithms: those in the biomarker strategy group received a default advisory to maintain treatment and those in the control group had their treatment adjusted according to the steps indicated by the trial algorithm. The primary outcome was the proportion of patients with corticosteroid dose reduction at week 48, in the intention-to-treat (ITT) population. Secondary outcomes were inhaled corticosteroid (ICS) dose at the end of the study; cumulative dose of ICS during the study; proportion of patients on maintenance oral corticosteroids (OCS) at study end; rate of protocol-defi
Lee S-W, Huang Y-C, Lin C-Y, et al., 2021, Impact of Annual Exposure to Polycyclic Aromatic Hydrocarbons on Acute Exacerbation Frequency in Asthmatic Patients, JOURNAL OF ASTHMA AND ALLERGY, Vol: 14, Pages: 81-90, ISSN: 1178-6965
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- Citations: 3
Qiu M, Wei S, Lai Z, et al., 2020, Early radiologic and bronchoscopic changes after bronchial thermoplasty in patients with severe asthma, EXPERIMENTAL AND THERAPEUTIC MEDICINE, Vol: 20, ISSN: 1792-0981
Gorlanova O, Tischhauser E, Adcock IM, et al., 2020, Discordant use of short-acting beta(2) agonists in children and adults with severe, uncontrolled asthma from the U-BIOPRED cohort, Pediatric Pulmonology, Pages: 1-3, ISSN: 1099-0496
Abdel-Aziz MI, Brinkman P, Vijverberg SJH, et al., 2020, eNose breath prints as a surrogate biomarker for classifying patients with asthma by atopy, Journal of Allergy and Clinical Immunology, Vol: 146, Pages: 1045-1055, ISSN: 0091-6749
BACKGROUND: Electronic noses (eNoses) are emerging point-of-care tools that may help in the subphenotyping of chronic respiratory diseases such as asthma. OBJECTIVE: We aimed to investigate whether eNoses can classify atopy in pediatric and adult patients with asthma. METHODS: Participants with asthma and/or wheezing from 4 independent cohorts were included; BreathCloud participants (n = 429), Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes adults (n = 96), Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes pediatric participants (n = 100), and Pharmacogenetics of Asthma Medication in Children: Medication with Anti-Inflammatory Effects 2 participants (n = 30). Atopy was defined as a positive skin prick test result (≥3 mm) and/or a positive specific IgE level (≥0.35 kU/L) for common allergens. Exhaled breath profiles were measured by using either an integrated eNose platform or the SpiroNose. Data were divided into 2 training and 2 validation sets according to the technology used. Supervised data analysis involved the use of 3 different machine learning algorithms to classify patients with atopic versus nonatopic asthma with reporting of areas under the receiver operating characteristic curves as a measure of model performance. In addition, an unsupervised approach was performed by using a bayesian network to reveal data-driven relationships between eNose volatile organic compound profiles and asthma characteristics. RESULTS: Breath profiles of 655 participants (n = 601 adults and school-aged children with asthma and 54 preschool children with wheezing [68.2% of whom were atopic]) were included in this study. Machine learning models utilizing volatile organic compound profiles discriminated between atopic and nonatopic participants with areas under the receiver operating characteristic curves of at least 0.84 and 0.72 in the training and validation sets, respectively. The unsupervised approach revealed t
Xiao D, Chen Z, Wu S, et al., 2020, Prevalence and risk factors of small airway dysfunction, and association with smoking, in China: findings from a national cross-sectional study, LANCET RESPIRATORY MEDICINE, Vol: 8, Pages: 1081-1093, ISSN: 2213-2600
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- Citations: 55
Haji G, Wiegman C, Michaeloudes C, et al., 2020, Mitochondrial dysfunction in airways and quadriceps muscle of patients with Chronic Obstructive Pulmonary Disease, Respiratory Research, Vol: 21, ISSN: 1465-9921
BackgroundMitochondrial damage and dysfunction have been reported in airway and quadriceps muscle cells of patients with chronic obstructive pulmonary disease (COPD). We determined the concomitance of mitochondrial dysfunction in these cells in COPD.MethodsBronchial biopsies were obtained from never- and ex-smoker volunteers and COPD patients (GOLD Grade 2) and quadriceps muscle biopsies from the same volunteers in addition to COPD patients at GOLD Grade 3/4 for measurement of mitochondrial function.ResultsDecreased mitochondrial membrane potential (ΔΨm), increased mitochondrial reactive oxygen species (mtROS) and decreased superoxide dismutase 2 (SOD2) levels were observed in mitochondria isolated from bronchial biopsies from Grade 2 patients compared to healthy never- and ex-smokers. There was a significant correlation between ΔΨm and FEV1 (% predicted), transfer factor of the lung for carbon monoxide (TLCOC % predicted), 6-min walk test and maximum oxygen consumption. In addition, ΔΨm was also associated with decreased expression levels of electron transport chain (ETC) complex proteins I and II. In quadriceps muscle of Grade 2 COPD patients, a significant increase in total ROS and mtROS was observed without changes in ΔΨm, SOD2 or ETC complex protein expression. However, quadriceps muscle of GOLD Grade 3/4 COPD patients showed an increased mtROS and decreased SOD2 and ETC complex proteins I, II, III and V expression.ConclusionsMitochondrial dysfunction in the airways, but not in quadriceps muscle, is associated with airflow obstruction and exercise capacity in Grade 2 COPD. Oxidative stress-induced mitochondrial dysfunction in the quadriceps may result from similar disease processes occurring in the lungs.
Michaeloudes C, Seiffert J, Chen S, et al., 2020, Effect of silver nanospheres and nanowires on human airway smooth muscle cells: role of sulfidation, Nanoscale Advances, Vol: 2, Pages: 5635-5647, ISSN: 2516-0230
Background: The toxicity of inhaled silver nanoparticles on contractile and pro-inflammatory airway smooth muscle cells (ASMCs) that control airway calibre is unknown. We explored the oxidative activities and sulfidation processes of the toxic-inflammatory response. Method: Silver nanospheres (AgNSs) of 20 nm and 50 nm diameter and silver nanowires (AgNWs), short S-AgNWs, 1.5 μm and long L-AgNWs, 10 μm, both 72 nm in diameter were manufactured. We measured their effects on cell proliferation, mitochondrial reactive oxygen species (ROS) release and membrane potential, and also performed electron microscopic studies. Main results and findings: The greatest effects were observed for the smallest particles with the highest specific surface area and greatest solubility that were avidly internalised. ASMCs exposed to 20 nm AgNSs (25 μg mL−1) for 72 hours exhibited a significant decrease in DNA incorporation (−72.4%; p < 0.05), whereas neither the 50 nm AgNSs nor the s-AgNWs altered DNA synthesis or viability. There was a small reduction in ASMC proliferation for the smaller AgNS, although Ag+ at 25 μL mL−1 reduced DNA synthesis by 93.3% (p < 0.001). Mitochondrial potential was reduced by both Ag+ (25 μg mL−1) by 47.1% and 20 nm Ag NSs (25 μg mL−1) by 40.1% (*both at p < 0.05), but was not affected by 50 nm AgNSs and the AgNWs. None of the samples showed a change in ROS toxicity. However, malondialdehyde release, associated with greater total ROS, was observed for all AgNPs, to an extent following the geometric size (20 nm AgNS: 213%, p < 0.01; 50 nm AgNS: 179.5%, p < 0.01 and L-AgNWs by 156.2%, p < 0.05). The antioxidant, N-acetylcysteine, prevented the reduction in mitochondrial potential caused by 20 nm AgNSs. The smaller nanostructures were internalised and dissolved within the ASMCs with the formation of non-reactive silver sulphide (Ag2S) on their surface, but with very little uptake of L-AgNWs. When A
Kermani NZ, Pavlidis S, Xie J, et al., 2020, Instability of sputum molecular phenotypes in U-BIOPRED severe asthma, European Respiratory Journal, Vol: 57, Pages: 1-5, ISSN: 0903-1936
Roberts G, Fontanella S, Selby A, et al., 2020, Connectivity patterns between multiple allergen specific IgE antibodies and their association with severe asthma, Journal of Allergy and Clinical Immunology, Vol: 146, Pages: 821-830, ISSN: 0091-6749
BACKGROUND: Allergic sensitization is associated with severe asthma, but assessment of sensitization is not recommended by most guidelines. OBJECTIVE: We hypothesized that patterns of IgE responses to multiple allergenic proteins differ between sensitized participants with mild/moderate and severe asthma. METHODS: IgE to 112 allergenic molecules (components, c-sIgE) was measured using multiplex array among 509 adults and 140 school-age and 131 preschool children with asthma/wheeze from the Unbiased BIOmarkers for the PREDiction of respiratory diseases outcomes cohort, of whom 595 had severe disease. We applied clustering methods to identify co-occurrence patterns of components (component clusters) and patterns of sensitization among participants (sensitization clusters). Network analysis techniques explored the connectivity structure of c-sIgE, and differential network analysis looked for differences in c-sIgE interactions between severe and mild/moderate asthma. RESULTS: Four sensitization clusters were identified, but with no difference between disease severity groups. Similarly, component clusters were not associated with asthma severity. None of the c-sIgE were identified as associates of severe asthma. The key difference between school children and adults with mild/moderate compared with those with severe asthma was in the network of connections between c-sIgE. Participants with severe asthma had higher connectivity among components, but these connections were weaker. The mild/moderate network had fewer connections, but the connections were stronger. Connectivity between components with no structural homology tended to co-occur among participants with severe asthma. Results were independent from the different sample sizes of mild/moderate and severe groups. CONCLUSIONS: The patterns of interactions between IgE to multiple allergenic proteins are predictors of asthma severity among school children and adults with allergic asthma.
Ramu S, Calven J, Michaeloudes C, et al., 2020, TLR3/TAK1 signalling regulates rhinovirus-induced interleukin-33 in bronchial smooth muscle cells, ERJ OPEN RESEARCH, Vol: 6
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- Citations: 4
Wu S-M, Feng P-H, Chuang H-C, et al., 2020, Impaired lnc-IL7R modulatory mechanism of Toll-like receptors is associated with an exacerbator phenotype of chronic obstructive pulmonary disease, FASEB JOURNAL, Vol: 34, Pages: 13317-13332, ISSN: 0892-6638
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- Citations: 5
Orton CM, Garner JL, Shah TA, et al., 2020, Metered Cryospray Modulates Bronchial Epithelial Gene Expression in Patients with Chronic Obstructive Pulmonary Disease, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Marshall D, Salciccioli J, Dobson P, et al., 2020, European Trends in Chronic Obstructive Pulmonary Disease Mortality and Incidence rates 2001 to 2017, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Wang C-H, Huang Y-C, Lee C-L, et al., 2020, Impact of air pollutant of polycyclic aromatic hydrocarbons (PAHs) on the yearly decline of pulmonary in patients with asthma, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Sheng TF, Huang Y-C, Lee S-W, et al., 2020, Impact of PAHs exposure on exacerbation frequency in asthma using a new grid-scale simulation of PM2.5-PAHs distribution, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Melen E, Hallberg J, Backman H, et al., 2020, Spirometric phenotypes from early childhood to young adulthood - A CADSET (Chronic Airway Disease Early Stratification) study, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Wheelock C, Reinke S, Kolmert J, et al., 2020, Urinary metabolomics-profiling of the U-BIOPRED asthma study identified biochemical clusters associated with asthma severity, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Adcock IM, Sun K, Kermani NZ, et al., 2020, A CADSET WP4 transcriptomic analysis of Asthma and COPD overlap, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Tiotiu A, Badi Y, Kermani NZ, et al., 2020, Differential mast cell activation by transcriptomic signature analysis in the U-BIOPRED severe asthma cohort, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Wiegman CH, Li F, Ryffel B, et al., 2020, Oxidative Stress in Ozone-Induced Chronic Lung Inflammation and Emphysema: A Facet of Chronic Obstructive Pulmonary Disease, Frontiers in Immunology, Vol: 11
Prihandoko R, Kaur D, Wiegman CH, et al., 2020, Pathophysiological regulation of lung function by the free fatty acid receptor FFA4, Science Translational Medicine, Vol: 12, Pages: 1-13, ISSN: 1946-6234
Increased prevalence of inflammatory airway diseases including asthma and chronic obstructive pulmonary disease (COPD) together with inadequate disease control by current frontline treatments means that there is a need to define therapeutic targets for these conditions. Here, we investigate a member of the G protein-coupled receptor family, FFA4, that responds to free circulating fatty acids including dietary omega-3 fatty acids found in fish oils. We show that FFA4, although usually associated with metabolic responses linked with food intake, is expressed in the lung where it is coupled to Gq/11 signaling. Activation of FFA4 by drug-like agonists produced relaxation of murine airway smooth muscle mediated at least in part by the release of the prostaglandin E2 (PGE2) that subsequently acts on EP2 prostanoid receptors. In normal mice, activation of FFA4 resulted in a decrease in lung resistance. In acute and chronic ozone models of pollution-mediated inflammation and house dust mite and cigarette smoke-induced inflammatory disease, FFA4 agonists acted to reduce airway resistance, a response that was absent in mice lacking expression of FFA4. The expression profile of FFA4 in human lung was similar to that observed in mice, and the response to FFA4/FFA1 agonists similarly mediated human airway smooth muscle relaxation ex vivo. Our study provides evidence that pharmacological targeting of lung FFA4, and possibly combined activation of FFA4 and FFA1, has in vivo efficacy and might have therapeutic value in the treatment of bronchoconstriction associated with inflammatory airway diseases such as asthma and COPD.
Kolmert J, Gómez C, Balgoma D, et al., 2020, Urinary leukotriene E4 and prostaglandin D2 metabolites increase in adult and childhood severe asthma characterized by type-2 inflammation, American Journal of Respiratory and Critical Care Medicine, Vol: 203, Pages: 37-53, ISSN: 1073-449X
RATIONALE: New approaches are needed to guide personalized treatment of asthma. OBJECTIVE: To test if urinary eicosanoid metabolites can direct asthma phenotyping. METHODS: Urinary metabolites of prostaglandins (PGs), cysteinyl-leukotrienes (LTs) and isoprostanes were quantified in the Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes (U-BIOPRED) study including 86 adults with mild-to-moderate asthma (MMA), 411 with severe asthma (SA), and 100 healthy controls (HC). Validation was performed internally in 302 SA subjects followed-up after 12-18 months, and externally in 95 adolescents with asthma. MEASUREMENT AND MAIN RESULTS: Metabolite levels in HC were unrelated to age, BMI and sex, except for the PGE2-pathway. Eicosanoid levels were generally greater in MMA relative to HC, with further elevations in SA. However, PGE2-metabolite levels were either the same or lower in male non-smoking asthmatics as in HC. Metabolite levels were unchanged in asthmatics adherent to oral corticosteroid treatment as documented by urinary prednisolone detection, whereas SA treated with omalizumab had lower levels of LTE4 and the PGD2 metabolite 2,3-dinor-11β-PGF2α. High levels of LTE4 and PGD2-metabolites were associated with lower lung-function, and increased levels of exhaled nitric oxide and eosinophil markers in blood, sputum and urine in U-BIOPRED and in adolescents with asthma. These type-2 (T2) asthma associations were reproduced in the follow-up visit of the U-BIOPRED study, and found to be as sensitive to detect T2 inflammation as the established biomarkers. CONCLUSIONS: Monitoring of urinary eicosanoids can identify T2 asthma and introduces a new non-invasive approach for molecular phenotyping of adult and adolescent asthma. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Niespodziana K, Borochova K, Pazderova P, et al., 2020, Toward personalization of asthma treatment according to trigger factors, JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol: 145, Pages: 1529-1534, ISSN: 0091-6749
Asthma is a severe and chronic disabling disease affecting more than 300 million people worldwide. Although in the past few drugs for the treatment of asthma were available, new treatment options are currently emerging, which appear to be highly effective in certain subgroups of patients. Accordingly, there is a need for biomarkers that allow selection of patients for refined and personalized treatment strategies. Recently, serological chip tests based on microarrayed allergen molecules and peptides derived from the most common rhinovirus strains have been developed, which may discriminate 2 of the most common forms of asthma, that is, allergen- and virus-triggered asthma. In this perspective, we argue that classification of patients with asthma according to these common trigger factors may open new possibilities for personalized management of asthma.
Carlsten C, Salvi S, Wong GWK, et al., 2020, Personal strategies to minimise effects of air pollution on respiratory health: advice for providers, patients and the public, EUROPEAN RESPIRATORY JOURNAL, Vol: 55, ISSN: 0903-1936
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- Citations: 55
Khusial RJ, Honkoop PJ, Usmani O, et al., 2020, Effectiveness of myAirCoach: A mHealth Self-Management System in Asthma, JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE, Vol: 8, Pages: 1972-+, ISSN: 2213-2198
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- Citations: 23
Song W-J, Chung KF, 2020, Pharmacotherapeutic Options for Chronic Refractory Cough, EXPERT OPINION ON PHARMACOTHERAPY, Vol: 21, Pages: 1345-1358, ISSN: 1465-6566
Xie J, Zhang J, Zhang X, et al., 2020, Cough in hypereosinophilic syndrome: case report and literature review, BMC PULMONARY MEDICINE, Vol: 20, ISSN: 1471-2466
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- Citations: 6
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