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Poorly controlled asthma can affect neonatal outcomes including congenital anomalies, which can be reduced with appropriate asthma care during pregnancy. Although there is a concern regarding the safety of asthma medication use during pregnancy and congenital anomalies, the risk of uncontrolled asthma outweighs any potential risks of controller and reliever medication use. Patient education before and during pregnancy is critical to ensure good compliance to therapy and reduce the risk of poor asthma control.

The alarmin cytokines thymic stromal lymphopoietin (TSLP), interleukin (IL)-33 and IL-25 and are epithelial cell-derived mediators that contribute to the pathobiology and pathophysiology of asthma. Released from airway epithelial cells exposed to environmental triggers, the alarmins drive airway inflammation through the release of predominantly T2 cytokines from multiple effector cells. The upstream positioning of the alarmins is an attractive pharmacological target to block multiple T2 pathways important in asthma. Blocking the function of TSLP inhibits allergen-induced responses including bronchoconstriction, airway hyperresponsiveness and inflammation, and subsequent clinical trials of an anti-TSLP monoclonal antibody, tezepelumab, in asthma patients demonstrated improvements in lung function, airway responsiveness, inflammation, and importantly, a reduction in the rate of exacerbations. Notably, these improvements were observed in patients with T2-high and with T2-low asthma. Clinical trials blocking IL-33 and its receptor ST2 have also shown improvements in lung function and exacerbation rates, however the impact of blocking the IL-33/ST2 axis in T2-high versus T2-low asthma is unclear. To date there is no evidence that IL-25 blockade is beneficial in asthma. Despite considerable overlap in the cellular functions of IL-25, IL-33 and TSLP, they appear to have distinct roles in the immunopathology of asthma.

Background Cough is a common troublesome symptom in asthma which is neuronally mediated. Limosilactobacillus reuteri DSM-17938 (L. reuteri DSM-17938) is a probiotic shown to be effective in pre-clinical models at suppressing neuronal responses to capsaicin, a transient receptor potential vanilloid agonist (TRPV1). Objective Investigate the effects of DSM-17938 versus matched placebo on capsaicin-evoked coughs in mild allergic asthmatics. Methods We performed a 4-visit, randomized, double-blind, placebo-controlled, two-way cross-over study comparing full dose cough responses with inhaled capsaicin in mild allergic asthmatics after 1 month of treatment with DSM-17938 compared with matched placebo. Randomization and allocation to trial group were carried out by a central computer system. Histamine skin prick testing, airway hyper-responsiveness and inflammatory cells in induced sputum were measured at every visit. Blood was collected to extract PBMCs and stimulated with CD3/CD28 to ascertain the effects of DSM-17938 /placebo on T-cell cytokine responses. Results Seventeen subjects were recruited and 15 completed the study (8 females, mean age 27.3 years). There was no difference in the change in maximum capsaicin-evoked coughs (Emax) after treatment with L. reuteri DSM-17938 compared with placebo [mean difference 2.07 coughs (95% CI -2.77 to 6.91, p = .38) or relative changes in geometric mean ratios for the dose evoking at least half the Emax (ED50) [1.05 (95% CI 0.31-3.58, p = .94)], concentration evoking 2 coughs (C2) [0.63 (0.26-1.53), p = .28] and 5 coughs (C5) [0.79 (0.25-2.50), p = .67]. There was no effect on histamine skin prick wheal size, intensity of itch sensation, methacholine PC20, airway inflammation or T-cell responses after stimulation with CD3/CD28. There were no serious adverse events. One subject developed a mild upper respiratory tract infection and another mild transient nausea whilst on DSM-17938. Conclusion In this small study in adults with mild allergic asthma, we found no evidence that L. reuteri DSM-17938 has any systemic effects on airway nerves, smooth muscle, sputum inflammatory cells, skin responses or T-cell responses after oral consumption. Trial registration Clinicaltrials.gov Identifier: NCT03603522.

Asthma is a chronic disease of the airways characterized by inflammation, tightened muscles, and thickened airway walls leading to symptoms such as shortness of breath, chest tightness, and cough in patients. The increased risk of asthma in children of asthmatics parents supports the existence of genetic factors involved in the pathogenesis of this disease. Genome-wide association studies have discovered several single nucleotide polymorphisms associated with asthma. These polymorphisms occur within several genes and can contribute to different asthma phenotypes, affect disease severity, and clinical response to different therapies. The complexity in the etiology of asthma also results from interactions between environmental and genetic factors. Environmental exposures have been shown to increase the prevalence of asthma in individuals who are genetically susceptible. This review summarizes what is currently known about the genetics of asthma in relation to risk, response to common treatments, and gene-environmental interactions.

The allergen provocation test is an established model of allergic airway diseases, including asthma and allergic rhinitis, allowing the study of allergen-induced changes in respiratory physiology and inflammatory mechanisms in sensitised individuals as well as their associations. In the upper airways, allergen challenge is focused on the clinical and pathophysiological sequelae of the early allergic response, and is applied both as a diagnostic tool and in research settings. In contrast, bronchial allergen challenge has almost exclusively served as a research tool in specialised research settings with a focus on the late asthmatic response and the underlying type 2 inflammation. The allergen-induced late asthmatic response is also characterised by prolonged airway narrowing, increased nonspecific airway hyperresponsiveness and features of airway remodelling including the small airways, and hence allows the study of several key mechanisms and features of asthma. In line with these characteristics, allergen challenge has served as a valued tool to study the cross-talk of the upper and lower airways and in proof-of-mechanism studies of drug development. In recent years, several new insights into respiratory phenotypes and endotypes including the involvement of the upper and small airways, innovative biomarker sampling methods and detection techniques, refined lung function testing as well as targeted treatment options further shaped the applicability of the allergen provocation test in precision medicine. These topics, along with descriptions of subject populations and safety, in line with the updated Global Initiative for Asthma 2021 document, will be addressed in this review. ispartof: EUROPEAN RESPIRATORY JOURNAL vol:60 issue:2 ispartof: location:England status: published

Atopic dermatitis (AD) is the most common inflammatory skin condition. Skin barrier dysfunction is of major importance in AD because it facilitates allergen sensitization and systemic allergic responses. Long regarded as a pro-apoptotic protease, emerging studies indicate granzyme B (GzmB) to have extracellular roles involving the proteolytic cleavage of extracellular matrix, cell adhesion proteins, and basement membrane proteins. Minimally expressed in normal skin, GzmB is elevated in AD and is positively correlated with disease severity and pruritus. We hypothesized that GzmB contributes to AD through extracellular protein cleavage. A causative role for GzmB was assessed in an oxazolone-induced murine model of dermatitis, comparing GzmB−/− mice with wild-type mice, showing significant reductions in inflammation, epidermal thickness, and lesion formation in GzmB−/− mice. Topical administration of a small-molecule GzmB inhibitor reduced disease severity compared with vehicle-treated controls. Mechanistically, GzmB impaired epithelial barrier function through E-cadherin and FLG cleavage. GzmB proteolytic activity contributes to impaired epidermal barrier function and represents a valid therapeutic target for AD. Refereed/Peer-reviewed

Rationale: Group 2 innate lymphoid cells (ILC2s) are critical for type 2 inflammation. In murine models of asthma, some ILC2s remain activated in the absence of epithelial cell-derived cytokine signaling, implicating alternate stimulatory pathways. DR3 (death receptor 3), a member of the tumor necrosis factor receptor superfamily, is expressed on ILC2s. Genome-wide association studies report an association between DR3 ligand, TL1A (tumor necrosis factor-like protein 1A), and chronic inflammatory conditions.Objectives: We investigated the TL1A/DR3 axis in airway ILC2 biology in eosinophilic asthma.Methods: Stable subjects with mild asthma were subject to allergen inhalation challenge, and DR3 expression on sputum cells was assessed. We investigated cytokine regulation of DR3 expression on ILC2s and steroid sensitivity. Airway TL1A was assessed in sputum from subjects with mild asthma and subjects with prednisone-dependent severe eosinophilic asthma.Measurements and Main Results: There was a significant increase in sputum DR3+ ILC2s 24 hours after allergen challenge, and DR3 expression on ILC2s was upregulated by IL-2, IL-33, or TSLP in vitro. Stimulation with TL1A significantly increased IL-5 expression by ILC2s and was attenuated by dexamethasone, an effect that was negated in the presence of TSLP. Airway TL1A levels were increased 24 hours after allergen challenge in subjects with mild asthma but were significantly greater in those with severe eosinophilic asthma. The highest levels were detected in subjects with severe asthma with airway autoimmune responses. C1q+ immune complexes from the sputa of subjects with severe asthma with high autoantibody levels stimulated TL1A production by monocytes.Conclusions: The TL1A/DR3 axis is a costimulator of ILC2s in asthma, particularly in the airways of patients with a predisposition to autoimmune responses.

Asthma is a common medical condition that can frequently affect pregnancy, and thus optimal management of asthma in pregnancy is important for both mother and baby. This article reviews recent developments of asthma pharmacotherapy and provides emerging data on the safety of asthma controller medications and biological therapies in pregnancy. The authors highlight the clinical outcomes of asthma during pregnancy, and summarize emerging new data related to the influence of sex hormones and fetal sex on asthma severity.This review of asthma pharmacotherapy during pregnancy examines the recent guidelines and reports the most pertinent publications on safety data and asthma management.Asthma management during pregnancy follows the same principles as that of non-pregnant asthma. The available data for most asthma medications are reassuring, however there is a lack of adequate safety data available because pregnant women are generally excluded from clinical trials. More clarity is needed in guidelines regarding the management of asthma in pregnancy, and high-quality randomized control trials are required to strengthen the evidence base and inform future guidelines. In particular, safety studies examining biological therapies in pregnant women with severe asthma are needed.

Background The anti-interleukin 13 (IL-13) monoclonal antibody lebrikizumab improves lung function in patients with moderate-to-severe uncontrolled asthma, but its effects on airway inflammation and remodelling are unknown. CLAVIER was designed to assess lebrikizumab's effect on eosinophilic inflammation and remodelling. Objective To report safety and efficacy results from enrolled participants with available data from CLAVIER. Methods We performed bronchoscopy on patients with uncontrolled asthma before and after 12 weeks of randomized double-blinded treatment with lebrikizumab (n = 31) or placebo (n = 33). The pre-specified primary end-point was relative change in airway subepithelial eosinophils per mm2 of basement membrane (cells/mm2 ). Pre-specified secondary and exploratory outcomes included change in IL-13-associated biomarkers and measures of airway remodelling. Results There was a baseline imbalance in tissue eosinophils and high variability between treatment groups. There was no discernible change in adjusted mean subepithelial eosinophils/mm2 in response to lebrikizumab (95% CI, -82.5%, 97.5%). As previously observed, FEV1 increased after lebrikizumab treatment. Moreover, subepithelial collagen thickness decreased 21.5% after lebrikizumab treatment (95% CI, -32.9%, -10.2%), and fractional exhaled nitric oxide, CCL26 and SERPINB2 mRNA expression in bronchial tissues also reduced. Lebrikizumab was well tolerated, with a safety profile consistent with other lebrikizumab asthma studies. Conclusions & clinical relevance We did not observe reduced tissue eosinophil numbers in association with lebrikizumab treatment. However, in pre-specified exploratory analyses, lebrikizumab treatment was associated with reduced degree of subepithelial fibrosis, a feature of airway remodelling, as well as improved lung function and reduced key pharmacodynamic biomarkers in bronchial tissues. These results reinforce the importance of IL-13 in airway pathobiology and suggest that neutralization of IL-13 may reduce asthmatic airway remodelling. Clinical trial registration NCT02099656.

Thymic stromal lymphopoietin (TSLP), an epithelial cytokine (alarmin), is a central regulator of the immune response to inhaled environmental insults such as allergens, viruses and pollutants, initiating a cascade of downstream inflammation. There is compelling evidence that TSLP plays a major role in the pathology of asthma, and therapies that aim to block its activity are in development.We review studies conducted in humans and human cells, largely published in PubMed January 2010-October 2019, that investigated the innate and adaptive immune mechanisms of TSLP in asthma relevant to type 2-driven (eosinophilic/allergic) inflammation and non-type 2-driven (non-eosinophilic/non-allergic) inflammation, and the role of TSLP as a mediator between immune cells and structural cells in the airway. Clinical data from studies evaluating TSLP blockade are also discussed.The position of TSLP at the top of the inflammatory cascade makes it a promising therapeutic target in asthma. Systemic anti-TSLP monoclonal antibody therapy with tezepelumab has yielded positive results in clinical trials to date, reducing exacerbations and biomarkers of inflammation in patients across the spectrum of inflammatory endotypes. Inhaled anti-TSLP is an alternative route currently under evaluation. The long-term safety and efficacy of TSLP blockade need to be evaluated.

BackgroundThymic stromal lymphopoietin (TSLP) is a key upstream regulator driving allergic inflammatory responses. We evaluated the efficacy and safety of ecleralimab, a potent inhaled neutralising antibody fragment against human TSLP, using allergen inhalation challenge (AIC) in subjects with mild atopic asthma.MethodsThis was a 12-week, randomised, double-blind, placebo-controlled, parallel-design, multicentre allergen bronchoprovocation study conducted at 10 centres across Canada and Germany. Subjects aged 18–60 years with stable mild atopic asthma were randomised (1:1) to receive 4 mg once-daily inhaled ecleralimab or placebo. Primary end-points were the allergen-induced change in forced expiratory volume in 1 s (FEV1) during the late asthmatic response (LAR) measured by area under the curve (AUC3–7h) and maximum percentage decrease (LAR%) on day 84, and the safety of ecleralimab. Allergen-induced early asthmatic response (EAR), sputum eosinophils and fractional exhaled nitric oxide (FENO) were secondary and exploratory end-points.Results28 subjects were randomised to ecleralimab (n=15) or placebo (n=13). On day 84, ecleralimab significantly attenuated LAR AUC3–7hby 64% (p=0.008), LAR% by 48% (p=0.029), and allergen-induced sputum eosinophils by 64% at 7 h (p=0.011) and by 52% at 24 h (p=0.047) post-challenge. Ecleralimab also numerically reduced EAR AUC0–2h(p=0.097) and EAR% (p=0.105).FENOlevels were significantly reduced from baseline throughout the study (pConclusionEcleralimab significantly attenuated allergen-induced bronchoconstriction and airway inflammation, and was safe in subjects with mild atopic asthma.

BACKGROUND Genome-wide association studies have identified associations of the single nucleotide polymorphism rs1837253 in the thymic stromal lymphopoietin (TSLP) gene with asthma, allergic disease and eosinophilia. The TSLP gene encodes two isoforms, long and short, and previous studies have indicated functional differences between these two isoforms. OBJECTIVE We investigated the expression of these TSLP isoforms in response to a pro-inflammatory signal, and the role of the rs1837253 genotype in gene isoform regulation. METHODS We cultured nasal epithelial cells of asthmatic and non-asthmatic subjects and evaluated poly(I:C)-induced TSLP protein secretion using multiplex protein assays and gene expression profiles of the TSLP isoforms, and related genes using real-time qPCR. We correlated these profiles with rs1837253 genotype. RESULTS Asthmatic nasal epithelial cells exhibited increased TSLP protein secretion compared with nasal epithelial cells from healthy controls. The long TSLP isoform was more responsive to poly(I:C) stimulation. Additionally, the minor T allele of rs1837253 was less inducible than the major C allele, suggesting differential regulation; this may explain the "protective" effects of the T allele in asthma. CONCLUSION Our results provide important insights into the differential regulation and function of TSLP isoforms, including the role of TSLP rs1837253 polymorphisms in allergic inflammatory processes. CLINICAL RELEVANCE The key finding on the influence of TSLP genetic variation on disease expression/endotype could provide basis for investigation into targeted biologics for anti-TSLP therapies.

In recent decades, the worldwide prevalence of allergic disease has increased considerably. The atopic march is a model aimed at explaining the apparent progression of allergic diseases from atopic dermatitis (AD) to allergic asthma (AA) and to allergic rhinitis (AR). It hypothesizes that allergic disease begins, typically in children, with the development of AD, then AA, and finally progresses to AR. This theory has been widely studied in cross-sectional and long-term longitudinal studies and it has been found that as prevalence of AD declines, prevalence of AA increases. A similar relationship is reported between AA and AR. The legitimacy of the atopic march model is, however, currently debated. Epidemiological evidence and criticism of longitudinal studies point to an overstatement of the atopic march’s prevalence and incorrect mechanisms, opening a discussion for alternative models to better explain the pathophysiological and epidemiological processes that promote this progression of allergic diseases. Albeit, risk factors for the development and progression of allergic disease, particularly AD, are critical in identifying disease progression. Investigating the role of age, severity, family history, phenotype, and genetic traits may give a better indication into the progression of allergic diseases. In addition, studies following patients from infancy into adulthood and a general increase in longitudinal studies would help broaden the knowledge of allergic disease progression and the atopic march.

SummaryBackgroundAdenoviral (Ad)-vectored vaccines are typically administered via intramuscular injection to humans, but this route of delivery is unable to induce respiratory mucosal immunity which requires respiratory mucosal route of vaccination. However, inhaled aerosol delivery of Ad-vectored vaccines has remained poorly characterized and its ability to induce respiratory mucosal immunity in humans is still unknown. The goal of our study was to evaluate and compare the safety and immunogenicity of a human serotype 5 Ad-based tuberculosis (TB) vaccine (AdHu5Ag85A) delivered to healthy humans via inhaled aerosol or intramuscular injection.MethodsIn this open-labeled phase 1b trial, 31 healthy adults between 18 and 55 years of age with a history of BCG vaccination were enrolled at McMaster University Medical Centre, Hamilton, Ontario, Canada. AdHu5Ag85A was administered by a single-dose aerosol using the Aeroneb® Solo Vibrating Mesh Nebulizer or by intramuscular (IM) injection; 11 in the low dose (LD, 1×106 PFU) aerosol group, 11 in the high dose (HD, 2×106 PFU) aerosol group and 9 in the IM (1×108 PFU) group. The primary outcome was safety of a single administration of vaccine delivered to the respiratory tract by aerosol or by IM injection. The vaccine-related local and systemic adverse events were collected from participants from a self-completed diary for 14 days after vaccination and at scheduled follow-up visits. Routine laboratory biochemical and haematological tests were measured at 2, 4 and 12 weeks after vaccination and lung function was measured at 2, 4, 8 and 12 weeks after vaccination. The secondary outcome was comparison of immunogenicity among the different routes and aerosol dose groups. Immunogenicity to aerosol or IM vaccination was measured both in the peripheral blood and bronchoalveolar lavage samples by Luminex, and cell surface and intracellular cytokine immunostaining. Anti-AdHu5 antibodies and neutralization titers were determined before and after vaccination using ELISA and bioassay, respectively. This trial is registered with ClinicalTrial.gov, NCT02337270.ResultsThe aerosol droplets generated by Aeroneb® Solo Nebulizer were mostly InterpretationInhaled aerosol delivery of Ad-vectored vaccine is a safe, economical and superior way to elicit respiratory mucosal immunity. The results of this study encourage further development of aerosol vaccine strategies against not only TB but also other respiratory pathogens including COVID-19.FundingThe Canadian Institutes for Health Research and the Natural Sciences and Engineering Research Council of Canada.Research in contextEvidence before this studyWe searched PubMed for published research articles without language or date restrictions by using search terms “adenovirus”, “aerosol” and “clinical trial” or “virus”, “vaccine”, “aerosol”, and “clinical trial”. Our search results indicate that adenoviral-vectored vaccine has rarely been delivered via inhaled aerosol into the respiratory tract of healthy humans. Adenoviral-vectored TB or HIV vaccine was delivered via inhaled aerosol to non-human primates, providing support for its further development for human application. An aerosolized adenoviral vector expressing CFTR was tested as a gene replacement therapeutic in cystic fibrosis patients. Recently, although an adenoviral-vectored COVID-19 vaccine was delivered via aerosol to humans, there were no evidence presented that it induced local mucosal immunity. Given the increased recognition of its value, inhaled aerosol has been explored in humans with non-adenoviral, viral vaccines against respiratory infections of global importance including measles and TB. However, since different aerosol technologies were used in these studies and aerosol characteristics including delivery efficiency vary according to the viral platform, aerosol delivery technology and its efficiency in inducing respiratory mucosal immunity remain to be established for administering adenoviral-vectored vaccine to healthy humans.Added value of this studyThis represents the first study to demonstrate the characteristics of a single-dose aerosolized human serotype 5 adenoviral-vectored vaccine, and its safety and immunogenicity in BCG-vaccinated healthy humans. It is also the first to show the superiority of inhaled aerosol immunization with this type of vaccine platform, over intramuscular (IM) route of immunization, in inducing respiratory mucosal immunity. Robust adaptive immune memory responses were induced in the respiratory tract with an aerosol vaccine dose up to 100 times smaller than the dose for IM immunization. Besides local mucosal immunity induced by aerosol immunization, it also induces levels of systemic immunity comparable to those by IM immunization. Also for the first time, we show that contrast to IM immunization, aerosol immunization does not increase either local or systemic anti-adenoviral neutralizing antibodies.Implications of all the available evidenceCollectively our findings show the technical feasibility, safety and potency of needle/pain-free delivery of a recombinant adenoviral-vectored vaccine to the respiratory tract of healthy adults. This vaccine strategy differs from parenteral route of immunization in its potency to elicit much desired respiratory mucosal immunity consisting of trained macrophages and tissue-resident memory T cells. The study provides the proof of concept to endorse inhaled aerosol vaccine strategies against pulmonary TB. Of further importance, as a number of currently authorized COVID-19 vaccines are also adenoviral-vectored, our study offers important technological details and scientific rationale for the development of inhalable next-generation COVID-19 vaccines aiming to induce all-around protective respiratory mucosal immunity in humans.

Asthma is a complex and chronic inflammatory disease of the airways, characterized by variable and recurring symptoms, reversible airflow obstruction, bronchospasm, and airway eosinophilia. As the pathophysiology of asthma is becoming clearer, the identification of new valuable drug targets is emerging. IL-5 is one of these such targets because it is the major cytokine supporting eosinophilia and is responsible for terminal differentiation of human eosinophils, regulating eosinophil proliferation, differentiation, maturation, migration, and prevention of cellular apoptosis. Blockade of the IL-5 pathway has been shown to be efficacious for the treatment of eosinophilic asthma. However, several other inflammatory pathways have been shown to support eosinophilia, including IL-13, the alarmin cytokines TSLP and IL-33, and the IL-3/5/GM-CSF axis. These and other alternate pathways leading to airway eosinophilia will be described, and the efficacy of therapeutics that have been developed to block these pathways will be evaluated.

Background: Asthma is a chronic disease of the airways characterised by airway remodelling, inflammation and mucus production. Airway macrophages (AMs) form a first line of defence against inhaled pathogen. In steady state and in response to pathogen, AM phenotype and function are underpinned by changes in cellular metabolism. The TCA cycle-derived metabolite itaconic acid (IA), synthesised by the enzyme aconitate decarboxylase (ACOD)-1, is a master regulator of macrophage function. We recently showed that IA limits pulmonary fibrosis in human and in murine models. However, its role in regulating asthma and allergic airway disease (AAD) is unknown. Methods: To study the kinetics of the Acod1/IA pathway in AAD, we analysed the metabolic profile of AMs ex vivo cultured with the aeroallergen house dust mite (HDM). Next, we measured airway inflammation, lung function and bronchoalveolar lavage (BAL) metabolite levels in WT and Acod1-/- mice. Finally, to investigate the role of IA in asthma, we measured metabolite levels in response to allergen challenge in sputum of mild asthmatics. Results:Ex vivo culture of AMs with HDM resulted in increased Acod1 expression and a more glycolytic phenotype. Continuous HDM exposure of WT mice led to increased lung Acod1 expression accompanied by augmented IA levels in BAL. Upon exposure to aeroallergen Acod1-/- mice showed a lower eosinophil-to-neutrophil ratio compared to more eosinophilic WT controls, which was rescued by inhaled IA. Finally, analysis of sputum from people with mild asthma revealed an inverse relationship between neutrophil numbers and IA levels. Conclusion: Our data indicate that the Acod1/IA pathway is highly induced during AAD and regulates the balance between neutrophil and eosinophil recruitment in response to inhaled allergen.

BACKGROUND Allergic rhinitis is characterized by rhinorrhea, nasal congestion, sneezing and nasal pruritus. Group 2 innate lymphoid cells (ILC2s), CD4+ T cells and eosinophils in nasal mucosa are increased significantly after nasal allergen challenge (NAC). Effects of intranasal corticosteroids (INCS) on ILC2s remain to be investigated. METHODS Subjects (n = 10) with allergic rhinitis and mild asthma were enrolled in a single-blind, placebo-controlled, sequential treatment study and treated twice daily with intranasal triamcinolone acetonide (220 µg) or placebo for 14 days, separated by a 7-day washout period. Following treatment, subjects underwent NAC and upper airway function was assessed. Cells from the nasal mucosa and blood, sampled 24 h post-NAC, underwent flow cytometric enumeration for ILC2s, CD4+ T and eosinophil progenitor (EoPs) levels. Cell differentials and cytokine levels were assessed in nasal lavage. RESULTS Treatment with INCS significantly attenuated ILC2s, IL-5+ /IL-13+ ILC2s, HLA-DR+ ILC2s and CD4+ T cells in the nasal mucosa, 24 h post-NAC. EoP in nasal mucosa was significantly increased, while mature eosinophils were significantly decreased, 24 h post-NAC in INCS versus placebo treatment arm. Following INCS treatment, IL-2, IL-4, IL-5 and IL-13 were significantly attenuated 24 h post-NAC accompanied by significant improvement in upper airway function. CONCLUSION Pre-treatment with INCS attenuates allergen-induced increases in ILC2s, CD4+ T cells and terminal differentiation of EoPs in the nasal mucosa of allergic rhinitis patients with mild asthma, with little systemic effect. Attenuation of HLA-DR expression by ILC2s may be an additional mechanism by which steroids modulate adaptive immune responses in the upper airways.

Allergic asthma is triggered by inhalation of environmental allergens resulting in bronchial constriction and inflammation, which leads to clinical symptoms such as wheezing, coughing, and difficulty breathing. Asthmatic airway inflammation is initiated by inflammatory mediators released by granulocytic cells. However, the immunoglobulin E (IgE) antibody is necessary for the initiation of the allergic cascade, and IgE is produced and released exclusively by memory B cells and plasma cells. Acute allergen exposure has also been shown to increase IgE levels in the airways of patients diagnosed with allergic asthma; however, more studies are needed to understand local airway inflammation. Additionally, regulatory B cells (B

Allergic asthma is triggered by inhalation of environmental allergens resulting in bronchial constriction and inflammation, which leads to clinical symptoms such as wheezing, coughing, and difficulty breathing. Asthmatic airway inflammation is initiated by inflammatory mediators released by granulocytic cells. However, the immunoglobulin E (IgE) antibody is necessary for the initiation of the allergic cascade, and IgE is produced and released exclusively by memory B cells and plasma cells. Acute allergen exposure has also been shown to increase IgE levels in the airways of patients diagnosed with allergic asthma; however, more studies are needed to understand local airway inflammation. Additionally, regulatory B cells (Bregs) have been shown to modulate IgE-mediated inflammatory processes in allergic asthma pathogenesis, particularly in mouse models of allergic airway disease. However, the levels and function of these IgE+ B cells and Bregs remain to be elucidated in human models of asthma. The overall objective for this chapter is to provide detailed methodological, and insightful technological advances to study the biology of B cells in allergic asthma pathogenesis. Specifically, we will describe how to investigate the frequency and function of IgE+ B cells and Bregs in allergic asthma, and the kinetics of these cells after allergen exposure in a human asthma model.

PURPOSE OF REVIEW: Allergen bronchoprovocation test (ABT) has been used to study asthma pathophysiology and as a disease-modelling tool to assess the properties and efficacy of new asthma drugs. In view of the complexity and heterogeneity of asthma, which has driven the definition of several phenotypes and endotypes, we aim to discuss the role of ABT in the era of precision medicine and provide guidance for clinicians how to interpret and use available data to understand the implications for the benefits of asthma treatment. RECENT FINDINGS: In this review, we summarize background knowledge and applications of ABT and provide an update with recent publications on this topic. In the past years, several studies have been published on ABT in combination with non-invasive and invasive airway samplings and innovative detection techniques allowing to study several inflammatory mechanisms linked to Th2-pathway and allergen-induced pathophysiology throughout the airways. SUMMARY: ABT is a valuable research tool, which has strongly contributed to precision medicine by helping to define allergen-triggered key inflammatory pathways and airway pathophysiology, and thus helped to shape our understanding of allergen-driven asthma phenotypes and endotypes. In addition, ABT has been instrumental to assess the interactions and effects of new-targeted asthma treatments along these pathways. (Less)

Introduction: CSJ117 is a potent neutralizing antibody fragment against human Thymic stromal lymphopoietin (TSLP), formulated as a PulmoSol™ engineered powder in hard capsules for delivery to the lungs via dry powder inhaler. Methods: In this double-blind, placebo-controlled study, 28 mild, atopic asthmatics meeting elibility criteria were randomized to receive 4mg CSJ117 (n = 15) or placebo (n = 13) inhaled daily for 12 weeks. Allergen inhalation challenge (AIC) was conducted at screening, day 42 and day 84. The primary efficacy variable was the late asthmatic response (LAR), measured 3 to 7 hours after AIC at day 84. Other outcomes included the early asthmatic response (EAR) measured within 2 hours after AIC, fractional exhaled nitric oxide (FeNO) level, and sputum eosinophils. Data were analyzed using repeated measures ANCOVA (β=10%) and one-sided tests (α=10%). Results: CSJ117 attenuated allergen-induced LAR and EAR at day 84. The time-adjusted AUC percentage decrease and the maximum decrease in FEV1 from pre-AIC were lower in the CSJ117 group compared to placebo (4.20% vs 11.38%, p = 0.008, and 9.28% vs 17.70%, P=0.029, during LAR; 12.83% vs 17.09%, P = 0.097, and 25.48% vs 30.90%, P = 0.105, during EAR). CSJ117 significantly attenuated the allergen-induced increase in % sputum eosinophils after AIC on day 84. CSJ117 significantly reduced FeNO before AIC at Day 83, but not the allergen-induced change. Conclusion: CSJ117 reduced allergen-induced bronchoconstriction and sputum eosinophilia, and pre challenge FeNO levels. These findings demonstrate CSJ117’s ability to attenuate airway inflammation in allergic asthmatics and support further studies as an inhaled anti-TSLP.

Asthma is a common chronic airway inflammatory disease characterized by diverse inflammatory events leading to airway hyperresponsiveness and reversible airflow obstruction. Corticosteroids have been the mainstay for asthma treatment due to their broad anti-inflammatory actions; however, other medications such as phosphodiesterase 4 inhibitors also demonstrate anti-inflammatory activity in the airways.This review describes tissue expression of phosphodiesterase 4 in the airways, the different phosphodiesterase 4 isoenzymes identified, and the anti-inflammatory activities of phosphodiesterase 4 inhibition in asthma and related findings in chronic obstructive pulmonary disease (COPD). The authors further review clinical trials demonstrating that drugs such as roflumilast have an excellent safety profile and efficacy in patients with asthma and COPD.Phosphodiesterase 4 inhibitors suppress the activity of immune cells, an effect similar to corticosteroids although by acting through different anti-inflammatory pathways and uniquely blocking neutrophilic inflammation. Roflumilast and other phosphodiesterase 4 inhibitors have been shown to provide additive protection in asthma when added to corticosteroid and anti-leukotriene treatment. Developmental drugs with dual phosphodiesterase 3 and 4 inhibition are thought to be able to provide bronchodilation and anti-inflammatory activities and will consequently be pushed forward in their clinical development for the treatment of asthma and COPD.