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This article compares the expression of SARS-CoV-2 receptors in the upper and lower airways of individuals with allergic asthma. The study found that the receptors ACE2 and TMPRSS2 were more abundant in the bronchial tissue of allergic asthmatics compared to healthy controls and nasal tissue of individuals with allergic rhinitis. Additionally, the levels of alarmin cytokines IL-33 and TSLP were higher in the bronchial tissue of allergic asthmatics. These findings suggest that individuals with allergic airway disease may have a higher number of viral entry receptors in their airways. However, despite these findings, asthmatic patients have been shown to have a lower risk of COVID-19 infection, which may be influenced by various factors. Further research is needed to fully understand the mechanisms underlying this lower risk and its implications for COVID-19 management in individuals with allergic airway disease. [Extracted from the article]

This article examines the protein expression of ACE2 and TMPRSS2 receptors in the airways of individuals with allergic asthma and allergic rhinitis after allergen challenge. The study found that allergen challenge led to a significant reduction in the number of cells expressing ACE2 and TMPRSS2 receptors in the bronchial tissue of individuals with allergic asthma. However, no significant changes were observed in the nasal tissue of individuals with allergic rhinitis. The authors hypothesized that elevated levels of IL-13, a type 2 cytokine, after allergen challenge may regulate ACE2 protein expression in the airways. The study suggests that while IL-13 may dampen ACE2 and TMPRSS2 receptor expression, other factors contribute to the rate of SARS-CoV-2 infectivity and hospitalization in individuals with asthma. [Extracted from the article]

Background: Similar immune responses in the nasal and bronchial mucosa implies that nasal allergen challenge (NAC) is a suitable early phase experimental model for drug development targeting allergic rhinitis (AR) and asthma. We assessed NAC reproducibility and the effects of intranasal corticosteroids (INCS) on symptoms, physiology, and inflammatory mediators. Methods: 20 participants with mild atopic asthma and AR underwent three single blinded nasal challenges each separated by three weeks (NCT03431961). Cohort A (n = 10) underwent a control saline challenge, followed by two allergen challenges. Cohort B (n = 10) underwent a NAC with no treatment intervention, followed by NAC with 14 days pre‐treatment with saline nasal spray (placebo), then NAC with 14 days pre‐treatment with INCS (220 μg triamcinolone acetonide twice daily). Nasosorption, nasal lavage, blood samples, forced expiratory volume 1 (FEV1), total nasal symptom score (TNSS), peak nasal inspiratory flow (PNIF) were collected up to 24 h after NAC. Total and active tryptase were measured as early‐phase allergy biomarkers (≤30 min) and IL‐13 and eosinophil cell counts as late‐phase allergy biomarkers (3–7 h) in serum and nasal samples. Period‐period reproducibility was assessed by intraclass correlation coefficients (ICC), and sample size estimates were performed using effect sizes measured after INCS. Results: NAC significantly induced acute increases in nasosorption tryptase and TNSS and reduced PNIF, and induced late increases in nasosorption IL‐13 with sustained reductions in PNIF. Reproducibility across NACs varied for symptoms and biomarkers, with total tryptase 5 min post NAC having the highest reproducibility (ICC = 0.91). Treatment with INCS inhibited NAC‐induced IL‐13 while blunting changes in TNSS and PNIF. For a similar crossover study, 7 participants per treatment arm are needed to detect treatment effects comparable to INCS for TNSS. Conclusion: NAC‐induced biomarkers and symptoms are reproducible and responsive to INCS. NAC is suitable for assessing pharmacodynamic activity and proof of mechanism for drugs targeting allergic inflammation. [ABSTRACT FROM AUTHOR]

The alarmin cytokines thymic stromal lymphopoietin (TSLP), interleukin (IL)‐33, and IL‐25 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 the considerable overlap in the cellular functions of IL‐25, IL‐33, and TSLP, they appear to have distinct roles in the immunopathology of asthma. [ABSTRACT FROM AUTHOR]

In line with a previous study, we found elevated levels of sputum CD4 SP + sp CRth2 SP + sp T cells compared with HC (Figure 1A; Table S2), suggesting a role for Th2 cells in driving airway eosinophilia in NAEB. Steroid treatment is reported to increase ILC2s cell death, reduce capacity for cell proliferation, and cell trans-differentiation. Brightling CE et al2 reported that NAEB patients had increased proportion of interleukin (IL)-4 SP + sp CD4 SP + sp T cells in bronchoalveolar lavage fluid, suggesting the role of Th2 cells in NAEB. [Extracted from the article]

Keywords: asthma treatment; biologics; biomarkers EN asthma treatment biologics biomarkers 3556 3559 4 11/01/21 20211101 NES 211101 An "operational" definition of an exacerbation of asthma is a (sub)acute worsening of asthma symptoms that requires a change in treatment. Therefore, international guidelines emphasize not only appropriate treatment of the exacerbations, but to optimize baseline asthma treatment to improve asthma control to reduce future risk. Patients with mild asthma may develop a severe exacerbation (ranging from 0.2 to 2.9/patient/year),3 that may rarely even be fatal, and patients with severe asthma may have a mild or moderate exacerbation. [Extracted from the article]

Keywords: asthma; asthma treatment; biologics; clinical immunology; eosinophils EN asthma asthma treatment biologics clinical immunology eosinophils 2913 2916 4 09/03/21 20210901 NES 210901 ACKNOWLEDGEMENT The authors acknowledge Teva Branded Pharmaceutical Products R&D, Inc, for providing reslizumab Phase III clinical trial data on file. Association of antieosinophil therapy with decreased body mass index in patients with severe asthma: A preliminary retrospective analysis. However, eosinophils have recently been recognized to regulate adipocyte homeostasis and energy expenditure through mechanisms that are not well understood.2 It is not known what the effect of anti-eosinophil therapies are on weight and body mass index (BMI). [Extracted from the article]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Despite improvements in medications, devices and understanding of the disease, about half of all asthma patients worldwide remain inadequately controlled, suggesting the need for a new approach to asthma management. Poor adherence to prescribed maintenance therapy and over‐reliance on SABA reliever medication is a common cause of inadequate control. This article reviews published data from 6‐ to 12‐month, double‐blind, RCT and open‐label real‐world studies involving budesonide/formoterol maintenance and reliever therapy (MART) and relevant comparator approaches to asthma management, and considers how these compare in achieving the treatment goals described in guidelines. The data confirm that patients with asthma treated with budesonide/formoterol MART achieved the same or better asthma symptom control compared with ICS/LABA plus SABA regimens at similar or higher ICS doses, with consistently lower rates of exacerbations and considerably lower annual requirement for oral corticosteroids. These findings have been confirmed across a range of severities of persistent asthma. With the MART approach, maintenance dosing ensures coverage for day‐to‐day control, and the use of a reliever with anti‐inflammatory properties (budesonide/formoterol) provides extra doses of ICS as soon as symptoms prompt the use of reliever, resulting in a 40–50% reduction of exacerbations compared with an ICS‐based treatment approach plus as‐needed SABA as reliever. As‐needed, budesonide/formoterol has also recently been shown to be more effective as a reliever in mild asthma than SABA alone, reducing exacerbations by up to 64% in the SYGMA studies. [ABSTRACT FROM AUTHOR]

Background: It is suggested that airway fungi, in particular Aspergillus may impinge on clinical phenotype in asthma. Indeed, the term severe asthma with fungal sensitization (SAFS) has been coined. We aimed to ascertain whether the presence of fungi, in particular Aspergillus fumigatus, in the airway correlated with asthma severity and control. Furthermore, we aimed to determine whether traditional markers of Aspergillus sensitization related to the presence of Aspergillus within the airway. Methods: Sixty‐nine patients characterized by asthma severity (GINA) and level of control (ACQ‐7) underwent bronchoscopy and bronchoalveolar lavage (BAL). Serum was assessed for A fumigatus‐specific IgE and total IgE. Galactomannan and relevant cytokine levels were assessed in serum, plasma and BAL. BAL was analyzed for the presence of A fumigatus. Results: In BAL, fungi were visible by microscopy in 70% and present by qPCR in 86% of patients, while A fumigatus was detectable by qPCR in 46%. Plasma and BAL IL‐4, IL‐6, IL‐10, IL‐13 and TNF‐α correlated with BAL fungal presence, while plasma IL‐17 correlated with BAL fungal presence. Aspergillus positive BAL correlated with increased plasma and BAL IL‐6 and BAL IL‐13. There was no relationship between fungal airway presence and steroid dose, asthma severity or control. The presence of Aspergillus within the airway did not relate to serum IgE positivity for Aspergillus. Conclusions: Fungi were present in a large proportion of our asthmatic patients' airways, but their presence was not predicted by traditional markers of sensitization, nor did it appear to be related to measures of disease severity or control. [ABSTRACT FROM AUTHOR]

Rationale: The effort required to cycle and breathe intensify as power increases during incremental exercise. It is currently unclear how changes in FEV1 in the presence or absence of airflow limitation) impacts the intensity of dyspnea and leg effort. This is clinically important as the improvement in FEV1 is often the target for improving dyspnea. Objectives: To investigate the relationship between dyspnea (D), leg effort, power (P), and FEV1 with and without airflow limitation using direct psychophysical scaling performed during incremental exercise testing to symptom limited capacity. Methods: Retrospective analysis of consecutive patients over the age of 35 referred for cardio‐pulmonary exercise testing at McMaster University Medical Centre from 1988–2012.The modified Borg scale was used to measure dyspnea throughout incremental exercise testing. Measurements and results: 38,788 patients were included in the analysis [Mean Age 58.6 years (SD ±11.8), Males 61%, BMI 28.1 kg/m2 (SD ±5.1), FEV1 was 2.7 L (SD ±0.85), 95% predicted (SD ±20.4), FVC 3.4 L (SD ± 1.0), 94% predicted (SD ±17.0)], and 10.9% had airflow limitation (AL, FEV1/FVC < 70%). In a nonlinear regression analysis, the intensity of dyspnea increased in a positively accelerating manner with power and as the FEV1% predicted decreased: Dyspnea = 0.06 * Power1.03 * FEV1%Pred−0.66(r =.63). The intensity of leg effort increased with power and declining quadricep strength and FEV1% predicted: Leg Effort = 0.06 * Power1.22 * Quad−0.56*FEV1%Pred−0.39(r =.73). There was no independent effect of AL on dyspnea of leg effort. Conclusion: Power, quadriceps strength and FEV1 are the dominant factors contributing to dyspnea and leg effort, irrespective of the degree of airflow limitation. [ABSTRACT FROM AUTHOR]

The article discusses a 2019 study on the effects of sex on sputum and blood levels of canonical type-2 cells (ILC2) and CD4+T lymphocytes on the airways of adults with mild and severe asthma. Results show that age influences sex steroid levels, with menopause linked to female sex hormone decrease, and testosterone decline to age in males, and the negative influence of obesity on ILC2 numbers. Also noted is the non-influence of sex on differences in ILC2 and CD4+ T cells in asthma.

For the past 20 years, asthma pharmacotherapy has been described in clinical practice guidelines in terms of a stepwise approach, with medications and/or doses increased if asthma is not well-controlled, and reduced once good control is achieved and maintained. Although many patients with asthma are untreated, there are also significant problems with over-treatment once regular controller therapy is commenced. This increases the cost of treatment and exposes patients to unnecessary risks of side-effects. The present pro-con debate addresses the question of whether the stepwise approach itself leads to over-treatment. Two asthma experts discuss factors for and against this proposition, identify issues on which more research is needed, and suggest areas in which guidelines can be changed in order to facilitate more appropriate prescribing of asthma medications. These strategies include better validation of the concepts underlying asthma treatment recommendations, stronger recommendations that every treatment change should be followed up with a scheduled review using evidence-based assessment tools and incorporation of phenotype-specific considerations into treatment recommendations. In addition, the process for development and dissemination of clinical practice guidelines should ensure that recommendations are easily understood, feasible to implement, and relevant to everyday asthma care and the needs and concerns of patients and clinicians. [ABSTRACT FROM AUTHOR]

Background and objective: Cytotoxic T-lymphocyte antigen 4 (CTLA-4) signalling of regulatory T cells regulates mucosal lymphocyte tolerance and differentiation, and may therefore have a beneficial effect in allergic diseases such as asthma. The aim of this study was to evaluate the effects of fluticasone propionate (FP) on CD4+CD25+ T cell co-expression of CTLA-4 in the sputum of mild asthmatic subjects. Methods: Eleven mild, stable asthmatic subjects completed a double-blind, randomized, cross-over, placebo-controlled study to compare the effects of 14 days 200 µg twice daily FP and placebo. Before and after treatment, airway hyperresponsiveness was measured, and sputum was induced for measurements of CTLA-4+CD4+CD25+ cells, eosinophils and levels of IL-10, IL-13 and transforming growth factor (TGF)-β Results: FP treatment increased co-expression of CTLA-4 on sputum CD4+CD25+ cells from a mean (SEM) of 7.9% (1.8) to 12.7% (3.3) after 14 days treatment ( P < 0.05) compared with placebo. FP treatment also significantly increased IL-10 levels, reduced per cent sputum eosinophils, and reduced airway hyperresponsiveness ( P < 0.05). There was a significant negative correlation between the change in airway hyperresponsiveness and per cent sputum eosinophils ( P < 0.01), but no correlation with changes in CTLA-4+CD4+CD25+ cells ( P > 0.05). There was no change in the levels of sputum IL-13 or TGF-β Conclusions: The percentage of airway CTLA-4+CD4+CD25+ cells increased after FP treatment, coincident with improvements in airway inflammation and hyperresponsiveness. Whether improved asthma assessments are related to the increase in CTLA-4+CD4+CD25+ cells and thus improved regulation of T-cell tolerance and differentiation will require a larger sample size to determine. The normalization of CTLA-4+CD4+CD25+ cells in asthma may contribute to the management of this disease. [ABSTRACT FROM AUTHOR]

Keywords: adherence; asthma management; control EN adherence asthma management control 795 796 2 07/17/20 20200801 NES 200801 The primary goal of management is to achieve optimal asthma control, which consists of two domains. A major paradox of asthma management is that despite the availability of very effective and safe medications to treat asthma, many (perhaps most) asthma patients remain poorly controlled. By contrast, inhaled corticosteroids (ICS) effectively reduce eosinophilic airway inflammation, improve asthma control and reduce asthma exacerbation risk, even in patients with mild asthma. [Extracted from the article]

Objective and background: Few studies have assessed the effectiveness of inhaled corticosteroid therapy exclusively in Asian patients with asthma. The present analysis compared the efficacy of early intervention with inhaled budesonide in Caucasian and Asian patients over the first 3 years of the inhaled Steroid Treatment As Regular Therapy in early asthma study. Methods: Patients aged 5–66 years with mild persistent asthma of ≤2 years’ duration were randomized to 3 years of double-blind treatment with once-daily budesonide 200 µg (for patients aged <11 years) or 400 µg administered via Turbuhaler or placebo, plus usual asthma therapy. Results: Budesonide significantly improved asthma outcomes in both Caucasian ( n = 4661) and Asian ( n = 1995) patients compared with reference therapy (placebo plus usual asthma therapy). Budesonide reduced the risk of a first severe asthma-related event by 42% and 49% in Caucasian and Asian patients, respectively, over the 3-year treatment period ( P < 0.001 for both). Moreover, budesonide significantly increased symptom-free days, decreased nights with sleeping problems, improved pre- and postbronchodilator FEV1 and reduced the need for additional asthma medications of particular drug classes compared with reference therapy. Except for differences in the patterns of use of additional asthma medications, outcomes with budesonide and overall adverse events were similar in the Caucasian and Asian patient populations. Conclusion: Inhaled budesonide administered once daily in Asian patients with recent-onset, mild persistent asthma significantly improved asthma control and pulmonary function compared with reference therapy. Moreover, this effectiveness paralleled that observed in Caucasian patients. [ABSTRACT FROM AUTHOR]

Inhaled corticosteroids are known to be effective in persistent asthma, but their long-term effect in mild persistent disease of recent onset, which is particularly relevant in children, requires clarification. The objective of this study was to determine the long-term efficacy of regular inhaled low-dose budesonide in children aged <11 yrs with mild persistent asthma with onset within 2 yrs of enrollment. Children aged 5–10 yrs formed part of the population of the inhaled Steroid Treatment As Regular Therapy in early asthma (START) study, and they were randomized in a double-blind manner to treatment with once daily budesonide 200 μg or placebo via TurbuhalerTM in addition to usual clinical care and other asthma medication. The double-blind treatment phase continued for 3 yrs. Of the 1974 children, 1000 in the budesonide group and 974 in the placebo group, were analyzed for efficacy. Addition of once-daily budesonide to usual care was associated with a significant increase in the time to first severe asthma-related event (SARE) and significantly reduced risk of SARE over 3 yrs. The hazard ratio relative to usual care (placebo) was 0.60 (95% confidence interval: 0.40–0.90; p = 0.012), with a relative risk reduction of 40%. Children receiving budesonide also needed significantly less intervention with other inhaled corticosteroids (12.3% vs. 22.5% over 3 yrs; p < 0.01), with trends towards decreased usage of oral/systemic corticosteroids and inhaled short-acting β2-agonists. Budesonide treatment also had a significant beneficial effect on lung function relative to placebo. In conclusion, early intervention adding once-daily budesonide to usual care in children with mild, persistent asthma of recent onset reduces the long-term risk and frequency of SAREs and improves lung function compared with usual care alone. [ABSTRACT FROM AUTHOR]

For many years, effective therapy for the management of asthma has been available. Issues of adverse side effects and questionable patient compliance with current therapies have been seen as deterrents for proven beneficial agents such as the anti-inflammatory corticosteroids and the bronchodilating β2-agonists. As effective as available agents are, the goal of consistent efficacy and ease of use has fueled research into new therapies that are either easier to use or have a more favorable side effect profile. [ABSTRACT FROM PUBLISHER]

Background: Interleukin (IL)‐6 signalling has been implicated in allergic asthma by animal, genetic association and clinical studies. In this study, we tested the hypothesis that tocilizumab (TCZ), a human monoclonal antibody that blocks IL‐6 signalling, can prevent the development of allergen‐induced bronchoconstriction in humans. Methods: We performed a randomised, double‐blind, placebo‐controlled study, with eligible participants completing two allergen inhalation challenge tests, conducted before and after treatment with a single dose of TCZ or placebo. The primary efficacy endpoint was the magnitude of the late asthmatic response recorded between 3 and 7 after allergen challenge. The secondary efficacy endpoint was the early asthmatic response, measured 20 min to 2 h after allergen challenge. Results: A total of 66 patients enrolled between September 2014 and August 2017, when the trial was stopped for futility based on results from an interim analysis. Eleven patients fulfilled all eligibility criteria assessed at baseline and were subsequently randomised to the TCZ (n = 6) or placebo (n = 5) groups. Both the primary and secondary efficacy endpoints were not significantly different between the two groups. Five patients reported adverse events (AEs), three in the TCZ group (11 AEs) and two in the placebo group (four AEs). Only one AE was TCZ‐related (mild neutropenia), and there were no serious AEs. Significant treatment effects were observed for serum levels of C‐reactive protein, IL‐6 and soluble IL‐6R levels. Conclusion: In a small proof‐of‐concept clinical trial, we found no evidence that a single dose of tocilizumab was able to prevent allergen‐induced bronchoconstriction. (Trial registered in the Australian New Zealand Clinical Trials Registry, number ACTRN12614000123640). [ABSTRACT FROM AUTHOR]

Background: Eosinophil-lineage committed progenitor cells (EoP) migrate from the bone marrow and differentiate locally to provide an ongoing source of mature eosinophils in asthmatic inflammatory responses in the airways. Sputum levels of EoP are increased in asthmatics compared to normal controls suggesting an exaggerated eosinophilopoietic environment in the airways. Understanding what factors promote EoP traffic to the airways is important to understand the diathesis of asthma pathology. Interleukin (IL)-25, is an epithelial-derived cytokine that promotes type 2 inflammatory responses. We have previously shown that levels of IL-25 and expression of the IL-25 receptor (IL-17RA and IL-17RB) on mature eosinophils are greater in allergic asthmatics compared to atopic non-asthmatics and non-atopic normal controls. In addition, these levels were increased significantly increased following allergen inhalation challenge and physiologically relevant levels of IL-25 stimulated eosinophil degranulation, intracellular IL-5 and IL-13 expression and primed migration to eotaxin. The current study, examined the role of IL-25 on allergen-induced trafficking of EoP in atopic asthmatics. Methods: Asthmatics (n = 14) who developed allergen-induced early and late responses were enrolled in the study. Blood was collected at pre- and 24 h post-challenge. At each time point, surface expression of IL-17RA and IL-17RB on EoP was evaluated by flow cytometry. Migration assays examined the effect of IL-25 on EoP chemotactic responses, in vitro. In addition, IL-25 knockout ovalbumin (OVA) sensitized and challenged mice were studied to evaluate in vivo mobilization effects of IL-25 on newly formed EoP and mature eosinophils. Results: There was a significant increase in numbers of blood EoP expressing IL-17RB, 24 h post-allergen inhalation challenge in allergic asthmatics. Pre-exposure to IL-25 primed the migrational responsiveness of EoP to stromal cell-derived factor 1α. In OVA-sensitized mice, knocking out IL-25 significantly alleviated OVA-induced eosinophil infiltration in the airway and newly formed eosinophils were reduced in the lung. Conclusions: The findings of this study indicate a potential role for IL-25 in allergen-induced trafficking of EoP to the airways and local differentiation promoting tissue eosiniophilia in asthmatic responses. [ABSTRACT FROM AUTHOR]

Summary There is increasing evidence that primitive progenitors migrate from the bone marrow (BM) via the peripheral circulation to tissue sites where they undergo in situ differentiation to provide a continued source of effector cells, such as eosinophils, during an allergic inflammatory response. To study mechanisms of progenitor cell mobilization in allergic reactions, we investigated fluctuations in the expression of the eotaxin receptor, CC chemokine receptor 3 (CCR3), on CD34+ cells from stable asthmatics following allergen (i.e. antigen) challenge. BM aspirates were taken from seven early responder (ER) and 10 dual responder (DR) asthmatics who, following antigen challenge developed only an early bronchoconstrictor response and an early and late- bronchoconstrictor response, respectively. Expression of CCR3 was detected on primitive (CD34+ cells) and eosinophil-lineage committed progenitors (CD34+ interleukin-5 receptor alpha-subunit+ cells) by flow cytometry and confirmed by co-localization of CCR3 messenger RNA to CD34 immunopositive cells using in situ hybridization. When preantigen levels were compared to 24-hr postantigen levels, significant increases in BM CD34+ CCR3+ cells were detected in DR, who also developed a significant sputum and blood eosinophilia and increased methacholine airway responsiveness. In contrast, a significant attenuation of BM CD34+ CCR3+ cells was observed in ER. In a dose-dependent manner eotaxin, but not interleukin (IL)-5, stimulated CD34+ progenitor cell migration in vitro . This migrational response to eotaxin was abrogated by anti-CCR3 monoclonal antibody and primed by preincubation with IL-5. We propose that fluctuations in CCR3 expression on human BM CD34+ cells may facilitate chemokine-mediated progenitor cell mobilization to the peripheral circulation and the resultant development of pulmonary eosinophilia,... [ABSTRACT FROM AUTHOR]