Gail M Gauvreau

McMaster University, Hamilton, Ontario, Canada

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Publications (140)859.28 Total impact

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    ABSTRACT: The ATS guidelines for methacholine testing for the diagnosis of asthma recommends the two minute tidal breathing protocol with the Wright nebuliser, which produces more aerosol than required, generates a small particle size, and requires cleaning between tests. The objective was to evaluate methacholine testing using a disposable, breath-actuated AeroEclipse™ II, which produces aerosol during inspiration and was developed for single-patient use. Forty-six adult asthmatic subjects (19 male), aged 27.3 (SD 9.5) years, with FEV1 98.5 (SD 18.1) % of predicted participated in a randomised, crossover, observational study. Subjects were first screened using the Wright nebulizer, then assigned to 2 minutes of tidal breathing from the Wright or 20 seconds of tidal breathing from the AeroEclipse™ nebuliser on 2 separate days, in random order. Methacholine PC20 values were calculated by linear interpolation of log dose versus response curves, log-transformed, and compared using paired student t-test and Pearson correlation. The thirty eight subjects demonstrating reproducible PC20 measurements of within 1.5 doubling concentrations were included in the comparison. The geometric mean methacholine PC20 measured with the AeroEclipse™ nebuliser was approximately 1 doubling concentration lower than the geometric mean methacholine PC20 of the Wright nebuliser (p<0.05). The Pearson correlation coefficient between the two nebulisers was 0.86 (P<0.05). The PC20 measurements using the two nebulisers were highly correlated, however, the PC20 determined with the AeroEclipse™ nebuliser was significantly lower than those determined using the Wright nebuliser. clinicaltrials.gov NCT01919424.
    04/2015; DOI:10.1513/AnnalsATS.201412-571BC
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    ABSTRACT: Thymic stromal lymphopoietin (TSLP) and IL-33 are considered important initiators of type 2 immunity. In asthmatic patients allergic inflammatory responses are associated with increased lung homing of bone marrow-derived CD34(+) hematopoietic progenitor cells (HPCs), which include eosinophil lineage-committed progenitor cells. In this study we investigated the role of TSLP and IL-33 in the recruitment of progenitor cells to the airways in asthmatic subjects. We sought (i) to examine the effect of allergen inhalation challenge on expression levels of receptors for TSLP (thymic stromal lymphopoietin receptor [TSLPR] and CD127) and IL-33 (ST2) and (ii) investigate the functional effects of these cytokines on HPCs. Consenting patients with mild atopic asthma (n = 19) with an FEV1 of 70% or greater and methacholine PC20 of 16 mg/mL or less were recruited. Blood- and sputum-extracted progenitors were phenotyped by flow cytometry before and 24 hours after allergen challenge. Functional responses, including cytokine production and migration to TSLP and IL-33, were assessed in vitro. Significant increases in mature eosinophil, HPC, and eosinophil lineage-committed progenitor cell counts in sputum were observed 24 hours after allergen and were associated with a significant allergen-induced increase in HPCs expressing TSLPR, CD127, and ST2. Pre-exposure to TSLP and IL-33 primed the migration of HPCs to a potent progenitor cell chemoattractant, stromal cell-derived factor 1α (CXCL12). Incubation with TSLP and IL-33 stimulated significant production of IL-5 and IL-13, but not IL-4, by HPCs. This priming effect was inhibited by blocking antibodies to TSLPR and ST2, respectively, and IL-13 receptor α1 in both scenarios. In allergic asthmatic responses increased lung homing of HPCs may be orchestrated by TSLP and IL-33 through an IL-13-dependent axis. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
    Journal of Allergy and Clinical Immunology 02/2015; DOI:10.1016/j.jaci.2014.12.1918 · 11.25 Impact Factor
  • Gail M Gauvreau, Judah A Denburg
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    ABSTRACT: Mast cell, basophil, and eosinophil lineages all derive from CD34(+) hemopoietic stem cells; however, mast cells are derived from a distinct, nonmyeloid progenitor, while eosinophils and basophils share a common myeloid progenitor. These progenitors likely evolved from an ancestral leukocyte population involved in innate immunity and currently play a central role in the pathology of allergic disease. Advances in isolation and analysis of mast cell and basophil/eosinophil progenitor populations have been critical to understanding lineage commitment, differentiation, function, and transcriptional regulation of these cells and have provided a way of monitoring the effect of novel investigational therapies on these cell populations in samples of blood, bone marrow, and airway secretions.
    Methods in molecular biology (Clifton, N.J.) 01/2015; 1220:59-68. DOI:10.1007/978-1-4939-1568-2_4 · 1.29 Impact Factor
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    ABSTRACT: Rationale: Effective anti-inflammatory therapies are needed for the treatment of asthma, but preferably without the systemic adverse effects of glucocorticosteroids. Objectives: We evaluated the effect of an inhaled non-steroidal glucocorticoid receptor agonist, AZD5423, on allergen-induced responses. Methods : Twenty mild allergic asthmatic subjects were randomized to receive 7 days of treatment with nebulized AZD5423 (75 μg or 300 μg) once daily, budesonide 200 μg twice daily via Turbuhaler®, and placebo in a double-blind, four-period, cross-over design study (NCT01225549). Allergen challenge was performed on Day 6. Measurements: FEV1 was measured repeatedly for 7 hours post-allergen for early and late asthmatic responses. Sputum inflammatory cells were measured before and at 7h and 24h post-allergen, and methacholine airway responsiveness was measured before and 24h post-allergen. Main Results: AZD5423 significantly attenuated the fall in FEV1 during the late asthmatic response (both doses 8.7% fall) versus placebo (14% fall) (p<0.05) with no effect of budesonide (12.5% fall) versus placebo (p>0.05). There was no effect on the fall in FEV1 during early asthmatic response. AZD5423 300 μg and 75 μg significantly attenuated allergen-induced sputum eosinophilia by 63% and 61% at 7h, and by 46% and 34% at 24h post-allergen, respectively, versus placebo (all p<0.05). Budesonide did not reduce allergen-induced sputum eosinophilia versus placebo. AZD5423 at 300 μg significantly attenuated allergen-induced airway hyperresponsiveness at 24h post-allergen versus placebo (p<0.05). Both doses of AZD5423 were well tolerated. Conclusions: Seven days inhalation of the non-steroidal glucocorticoid receptor agonist AZD5423 effectively reduced allergen-induced responses in subjects with mild allergic asthma. Clinical trial registration available at www.clinicaltrials.gov, ID NCT01225549.
    American Journal of Respiratory and Critical Care Medicine 12/2014; 191(2). DOI:10.1164/rccm.201404-0623OC · 11.99 Impact Factor
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    ABSTRACT: Background: T helper (Th)17 cells may play a role in allergic asthma. This study assessed the effect of allergen inhalation challenge on circulating Th17 cells and related cytokines in allergic asthmatics. Methods: Peripheral blood mononuclear cells were collected from 16 atopic asthmatics before and 24 h after allergen challenge, as well as from 10 atopic nonasthmatics and 10 normal controls. Cells were stained for Th17 cytokines and their receptors (IL-17A, IL-17F, IL-21, IL-22, IL-17R, and IL-23R) using flow cytometry. Cytokine concentrations from cell culture supernatants were quantified using a multiplex assay for IL-17A, IL-17F, IL-21, IL-22, and IL-23. Results: At baseline, asthmatics had a higher percentage of circulating Th17 cells (1.2 ± 0.5%) compared to normal controls (0.9 ± 0.66%, p < 0.001) but not compared to atopic nonasthmatics (1.13 ± 0.5%). There was a significant increase in Th17 cells in asthmatics after allergen challenge to 1.55 ± 0.4% (p < 0.05) and a trend toward significance in IL-17R expression from 3.4 ± 4.3 to 6.86 ± 6.84% after allergen challenge (p = 0.06). There was also a significant reduction in IL-21-positive cells following allergen challenge from 3.46 ± 1.85 to 2.33 ± 1.37% (p < 0.001). There were no significant differences in IL-17F, IL-22 and IL-23R expression. The concentration of IL-17A in culture supernatant was significantly higher in asthmatics compared to normal controls and IL-17A significantly increased 24 h after allergen challenge. Conclusions: The increase of Th17 cells and IL-17A in atopic asthma after allergen inhalation challenge suggests a possible role for Th17 in allergen-induced airway responses. © 2014 S. Karger AG, Basel.
    International Archives of Allergy and Immunology 10/2014; 165(1):27-34. DOI:10.1159/000367789 · 2.43 Impact Factor
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    ABSTRACT: Elevated serum levels of both total and allergen-specific immunoglobulin E (IgE) correlate with atopic diseases such as allergic rhinitis and allergic asthma. Neutralization of IgE by anti-IgE antibodies can effectively treat allergic asthma. Preclinical studies indicate that targeting membrane IgE-positive cells with antibodies against M1 prime can inhibit the production of new IgE and significantly reduce the levels of serum IgE. We report results from two trials that investigated the safety, pharmacokinetics, and activity of quilizumab, a humanized monoclonal antibody targeting specifically the M1 prime epitope of membrane IgE, in subjects with allergic rhinitis (NCT01160861) or mild allergic asthma (NCT01196039). In both studies, quilizumab treatment was well tolerated and led to reductions in total and allergen-specific serum IgE that lasted for at least 6 months after the cessation of dosing. In subjects with allergic asthma who were subjected to an allergen challenge, quilizumab treatment blocked the generation of new IgE, reduced allergen-induced early and late asthmatic airway responses by 26 and 36%, respectively, and reduced allergen-induced increases in sputum eosinophils by ~50% compared with placebo. These studies indicate that targeting of membrane IgE-expressing cells with anti-M1 prime antibodies can prevent IgE production in humans.
    Science translational medicine 07/2014; 6(243):243ra85. DOI:10.1126/scitranslmed.3008961 · 14.41 Impact Factor
  • Brittany Watson, Gail M Gauvreau
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    ABSTRACT: Introduction: Epithelial cell-derived mediators have emerged as key players for instigating local remodeling and the associated cellular inflammation in asthmatic airways. In particular, the epithelial-derived cytokine, thymic stromal lymphopoietin (TSLP), has been identified as a master switch for allergic inflammation. Areas covered: TSLP is expressed by structural and immune cells at the site of allergen entry in the airways. Stimuli for release of TSLP include common triggers of asthma symptoms, and TSLP levels correlate with disease severity. TSLP regulates helper T cell 2 (Th2) humoral immunity through upregulating OX40L on dendritic cells (DCs), which drives Th2 lymphocytes; however, activation of several other cells by TSLP also supports the development of Th2 inflammation. Animal models of asthma demonstrate that increased levels of TSLP can induce many of the characteristics of asthma. Expert opinion: The work conducted to date supports a critical role of TSLP in the pathogenesis of allergic asthma. The first clinical trial to block the downstream effects of OX40L has shown reduced levels of circulating IgE and airway eosinophils, confirming the importance of TSLP-induced OX40L levels on DCs. Clinical trials with TSLP blockade are underway and will unequivocally confirm whether TSLP is indeed a key driver of allergic inflammation in asthma.
    Expert Opinion on Therapeutic Targets 07/2014; 18(7):771-85. DOI:10.1517/14728222.2014.915314 · 4.90 Impact Factor
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    ABSTRACT: Background The imbalance between Th17 and Treg cells has been studied in various diseases including allergic asthma but their roles have not been fully understood in the development of the late phase asthmatic response. Objectives To determine changes in Th17 and Treg cell numbers between isolated early responders (ERs) and dual responders (DRs) undergoing allergen inhalation challenge. To identify gene expression profiles associated with Th17 and Treg cells. Methods 14 participants (8 ERs and 6 DRs) with mild allergic asthma underwent allergen inhalation challenge. Peripheral blood was collected prior to and 2 hours post allergen challenge. DNA methylation analysis was used to quantifiy the relative frequencies of Th17, Tregs, total B cells, and total T cells. Gene expression from whole blood was measured using microarrays. Technical replication of selected genes was performed using nanoString nCounter Elements. Results The Th17/Treg ratio significantly increased in DRs compared to ERs post allergen challenge compared to pre-challenge. Genes significantly correlated to Th17 and Treg cell counts were inversely correlated with each other. Genes significantly correlated with Th17/Treg ratio included the cluster of genes of the leukocyte receptor complex located on chromosome 19q 13.4. Conclusions Th17/Treg imbalance post-challenge may contribute to the development of the late phase inflammatory phenotype.
    Allergy Asthma and Clinical Immunology 06/2014; 10(32). DOI:10.1186/1710-1492-10-32
  • Brittany Watson, Gail M Gauvreau
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    ABSTRACT: Introduction: Epithelial cell-derived mediators have emerged as key players for instigating local remodeling and the associated cellular inflammation in asthmatic airways. In particular, the epithelial-derived cytokine, thymic stromal lymphopoietin (TSLP), has been identified as a master switch for allergic inflammation.Areas covered: TSLP is expressed by structural and immune cells at the site of allergen entry in the airways. Stimuli for release of TSLP include common triggers of asthma symptoms, and TSLP levels correlate with disease severity. TSLP regulates helper T cell 2 (Th2) humoral immunity through upregulating OX40L on dendritic cells (DCs), which drives Th2 lymphocytes; however, activation of several other cells by TSLP also supports the development of Th2 inflammation. Animal models of asthma demonstrate that increased levels of TSLP can induce many of the characteristics of asthma.Expert opinion: The work conducted to date supports a critical role of TSLP in the pathogenesis of allergic asthma. The first clinical trial to block the downstream effects of OX40L has shown reduced levels of circulating IgE and airway eosinophils, confirming the importance of TSLP-induced OX40L levels on DCs. Clinical trials with TSLP blockade are underway and will unequivocally confirm whether TSLP is indeed a key driver of allergic inflammation in asthma.
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    ABSTRACT: Background Thymic stromal lymphopoietin (TSLP) is an epithelial-cell-derived cytokine that may be important in initiating allergic inflammation. AMG 157 is a human anti-TSLP monoclonal immunoglobulin G2λ that binds human TSLP and prevents receptor interaction. Methods In this double-blind, placebo-controlled study, we randomly assigned 31 patients with mild allergic asthma to receive three monthly doses of AMG 157 (700 mg) or placebo intravenously. We conducted allergen challenges on days 42 and 84 to evaluate the effect of AMG 157 in reducing the maximum percentage decrease in the forced expiratory volume in 1 second (FEV1). We also measured the fraction of nitric oxide in exhaled air, blood and sputum eosinophils, and airway hyperresponsiveness. The primary end point was the late asthmatic response, as measured 3 to 7 hours after the allergen challenge. Results AMG 157 attenuated most measures of allergen-induced early and late asthmatic responses. The maximum percentage decrease in the FEV1 during the late response was 34.0% smaller in the AMG-157 group than in the placebo group on day 42 (P=0.09) and 45.9% smaller on day 84 (P=0.02). In addition, patients receiving AMG 157 had significant decreases in levels of blood and sputum eosinophils before and after the allergen challenge and in the fraction of exhaled nitric oxide. There were 15 adverse events in the AMG-157 group, as compared with 12 in the placebo group; there were no serious adverse events. Conclusions Treatment with AMG 157 reduced allergen-induced bronchoconstriction and indexes of airway inflammation before and after allergen challenge. These findings are consistent with a key role for TSLP in allergen-induced airway responses and persistent airway inflammation in patients with allergic asthma. Whether anti-TSLP therapeutics will have clinical value cannot be determined from these data. (Funded by Amgen; ClinicalTrials.gov number, NCT01405963 .).
    New England Journal of Medicine 05/2014; DOI:10.1056/NEJMoa1402895 · 54.42 Impact Factor
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    ABSTRACT: l-Arginine metabolism including the nitric oxide (NO) synthase and arginase pathways is important in the maintenance of airways function. We have previously reported that accumulation of asymmetric dimethylarginine (ADMA) in airways, resulting in changes in l-arginine metabolism, contributes to airways obstruction in asthma and cystic fibrosis. Herein, we assessed l-arginine metabolism in airways of patients with chronic obstructive pulmonary disease (COPD). Lung function testing, measurement of fractional exhaled NO (FeNO) and sputum NO metabolites, as well as quantification of l-arginine metabolites (l-arginine, l-ornithine, l-citrulline, ADMA and symmetric dimethylarginine) using liquid chromatography-mass spectrometry (LC-MS) were performed. Concentrations of l-ornithine, the product of arginase activity, correlated directly with l-arginine and ADMA sputum concentrations. FeNO correlated directly with pre- and post-bronchodilator forced expiratory volume in one second (FEV1). Sputum arginase activity correlated inversely with total NO metabolite (NOx) and nitrite concentrations in sputum, and with pre- and post-bronchodilator FEV1. These findings suggest that ADMA in COPD airways results in a functionally relevant shift of l-arginine breakdown by the NO synthases towards the arginase pathway, which contributes to airway obstruction in these patients.
    International Journal of Molecular Sciences 04/2014; 15(4):6062-71. DOI:10.3390/ijms15046062 · 2.34 Impact Factor
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    ABSTRACT: PurposePPAR agonists have been suggested as novel therapeutics for the treatment of inflammatory lung disease, such as allergic asthma. Treatment with PPAR agonists have been shown to inhibit airway eosinophilia in murine models of allergic asthma, which can occur through several mechanisms including attenuated generation of chemoattractants (e.g. eotaxin) and decreased eosinophil migrational responses. In addition, studies report PPAR agonists can inhibit the differentiation of several cell types. Although to date, no studies have examined the effects of PPAR agonists on IL-5-induced eosinophil differentiation from hemopoietic progenitor cells.Methods Non-adherent mononuclear cells (NAMNCs) or CD34+ cells isolated from peripheral blood of allergic subjects were grown for 2 weeks in Methocult® cultures with IL-5 (10 ng/mL) and IL-3 (25 ng/mL) in the presence of 1-1000 nM PPARα agonist (GW9578), PPARβ/δ agonist (GW501516), PPARγ agonist (rosiglitazone) or diluent. The number of eosinophil/basophil colony forming units (Eo/B CFU) were quantified by light microscopy. The signaling mechanism involved was assessed by phosphoflow.ResultsBlood extracted CD34+ cells cultured with IL-5 or IL-5+IL-3 formed Eo/B CFU, which were significantly inhibited by rosiglitazone (100 nM, p<0.01) but not GW9578 or GW501516. In addition rosglitazone significantly inhibited IL-5-induced phosphorylation of ERK1/2.Conclusions We observed an inhibitory effect of rosiglitazone on eosinophil differentiation in vitro, mediated by attenuation of the ERK1/2 signalling pathway. These findings indicate that PPARγ agonist can attenuate tissue eosinophilia by interfering with local differentiative responses.This article is protected by copyright. All rights reserved.
    Immunology 03/2014; DOI:10.1111/imm.12280 · 3.74 Impact Factor
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    ABSTRACT: Dendritic cells (DCs) are professional antigen presenting cells that mediate the response to inhaled allergen. A major division in DC ontogeny exists between myeloid DCs (mDCs) and plasmacytoid DCs (pDCs). A subtype of mDC expressing thrombomodulin, termed myeloid DCs type 2 (mDC2s), has been identified in both the circulation and lung, and has recently been suggested to have a role in allergic asthma. To investigate changes in circulating and sputum mDC2s after allergen inhalation in subjects with asthma. Peripheral blood and induced sputum was obtained before and 3 hours, 7 hours, and 24 hours after inhalation of diluent and allergen from allergic asthmatic subjects who develop both allergen-induced early and late phase responses. mDC2s were measured by flow cytometry. Soluble BDCA-3 (thrombomodulin) was measured in sputum by ELISA. The number of sputum mDC2s significantly increased 24 hours after allergen challenge compared with diluent. The expression of BDCA-3 on sputum mDCs also increased, albeit non-significantly, at 7 hours and 24 hours after allergen. Soluble BDCA-3 in sputum and the number of circulating mDC2s were not different between allergen and diluent. mDC2s increase in the sputum of subjects with asthma after allergen challenge, suggesting this subtype of mDC is involved in the regulation of allergen responses in the lung. This article is protected by copyright. All rights reserved.
    Clinical & Experimental Allergy 02/2014; 44(7). DOI:10.1111/cea.12297 · 4.32 Impact Factor
  • Jeremy A Scott, Gail M Gauvreau, Hartmut Grasemann
    European Respiratory Journal 02/2014; 43(2):647-8. DOI:10.1183/09031936.00080313 · 7.13 Impact Factor
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    Pia Reece, Gail M Gauvreau, Roma Sehmi, Judah A Denburg
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    ABSTRACT: Intrauterine environmental exposures have been shown to influence neonatal immunity and subsequent allergic disease development. We have previously shown that fewer lipopolysaccharide (LPS)-stimulated eosinophil-basophil (Eo/B) colonies grow from cord blood (CB) of high-atopic risk infants, compared to low-atopic risk infants. In the present study, we investigated whether a surrogate ex vivo TH2 milieu (i.e., either IL-4 or IL-13) could represent an underlying mechanism to explain our previous findings. CB CD34+ cells from healthy donors were cultured with IL-4 or IL-13 (in combination with LPS) and assessed for Eo/B differentiation using methylcellulose cultures and flow cytometry for related intracellular signalling pathways. Pharmacological inhibitors were added to the methylcellulose cultures to determine the effect of blocking intracellular signalling in CB CD34+ cells in relation to Eo/B colony forming unit (CFU) formation. Stimulation of CD34+ cells with IL-4, but not IL-13, reduced Eo/B CFU formation in the presence of LPS; this was found to be dependent on IL-4Rα and not IL-13Rα1. Additionally, IL-4 reduced the expression of ERK 1/2 after LPS stimulation, which was recovered by inhibition of IL-4Rα. While IL-13 did not have an inhibitory effect on ERK 1/2 expression, inhibition of ERK 1/2 significantly reduced Eo/B CFU formation. Thus, the responsiveness of CB CD34+ progenitor cells to LPS is differentially regulated by the TH2 cytokines, IL-4 and IL-13. This may have implications for in utero interactions between placental-derived pro-allergic cytokines and neonatal progenitor cells influencing Eo/B-mediated inflammatory responses in early life.
    PLoS ONE 02/2014; 9(6):e100734. DOI:10.1371/journal.pone.0100734 · 3.53 Impact Factor
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    ABSTRACT: Nicotinic acetylcholine receptors (nAChRs) were identified on eosinophils and shown to regulate inflammatory responses, but nAChR expression on basophils has not been explored yet. We investigated surface receptor expression of nAChR α4, α7 and α1/α3/α5 subunits on basophils. Furthermore, we examined the effects of ASM-024, a synthetic nicotinic ligand, on in vitro anti-IgE and in vivo allergen-induced basophil activation. Basophils were enriched from the peripheral blood of allergic donors and the expression of nAChR subunits and muscarinic receptors was determined. Purified basophils were stimulated with anti-IgE in the presence of ASM-024 with or without muscarinic or nicotinic antagonists for the measurement of CD203c expression and histamine release. The effect of 9 days of treatment with 50 and 200 mg ASM-024 on basophil CD203c expression was examined in the blood of mild allergic asthmatics before and after allergen inhalation challenge. nAChR α4, α7 and α1/α3/α5 receptor subunit expression was detected on basophils. Stimulation of basophils with anti-IgE increased CD203c expression and histamine release, which was inhibited by ASM-024 (10(-5) to 10(-)(3) M, p < 0.05). The effect of ASM-024 was reversed in the presence of muscarinic and nicotinic antagonists. In subjects with mild asthma, ASM-024 inhalation significantly inhibited basophil CD203c expression measured 24 h after allergen challenge (p = 0.03). This study shows that ASM-024 inhibits IgE- and allergen-induced basophil activation through both nicotinic and muscarinic receptors, and suggests that ASM-024 may be an efficacious agent for modulating allergic asthma responses. © 2015 S. Karger AG, Basel.
  • Allergy Asthma and Clinical Immunology 01/2014; 10(Suppl 1):A46. DOI:10.1186/1710-1492-10-S1-A46
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    ABSTRACT: Background: Shortly after allergen exposure, the number of bone marrow (BM) and circulating CD34(+) progenitors increases. We aim to analyze the possible mechanism whereby the allergic reaction stimulates BM to release these effector cells in increased numbers. We hypothesize that mast cells (MCs) may play a predominant role in this process. Objective: To examine the effect of IgE-activated MCs on BM mesenchymal stromal cells which regulate proliferation and differentiation of CD34(+) progenitors. Methods: Primary MCs were derived from CD34(+) precursors and activated with IgE/anti-IgE. BM mesenchymal stromal cells were co-cultured with CD34(+) progenitor cells and stimulated with IL-1/TNF or IgE/anti-IgE-activated MCs in Transwell system. Results: BM mesenchymal stromal cells produce low level of thymic stromal lymphopoietin (TSLP) under steady state conditions, which is markedly increased by stimulation with proinflammatory cytokines IL-1 and TNF or IgE-activated MCs. The latter also triggers bone marrow-derived mesenchymal stromal cells production of G-CSF, and GM-CSF while inhibiting SDF-1. MC-activated mesenchymal stromal cells stimulate CD34(+) cells to proliferate and to regulate their expression of early allergy-associated genes. Conclusion and Clinical Relevance: This in vitro study indicates that IgE-activated MCs trigger BM mesenchymal stromal cells to release TSLP and hematopoietic growth factors and to regulate the proliferation and lineage commitment of CD34(+) precursor cells. The data predict that the effective inhibition of MCs should impair mobilization and accumulation of allergic effector cells and thereby reduce the severity of allergic diseases.
    Frontiers in Immunology 12/2013; 4:461. DOI:10.3389/fimmu.2013.00461
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    ABSTRACT: Background: Allergic asthma is an inflammatory airway disease in which Th2 cytokines play an important role. Epithelial-derived interleukin (IL)-25 has been suggested to be important in the maintenance of Th2-type responses. The effects of IL-25 are mediated by the IL-25 receptor, composed of two subunits, IL-17RA and IL-17RB. Eosinophils are effector cells in allergic asthma. The role of IL-25 in eosinophil function is unknown. This study examined the expression of IL-25 and its receptor on eosinophils in allergic asthmatics compared to atopic nonasthmatics and normal controls. Methods: The expression of IL-25, IL-17RA and IL-17RB on eosinophils, and levels of plasma IL-25 were measured in 14 normal control subjects, 15 atopic nonasthmatics and 14 mild allergic asthmatics. Results: The expression of IL-17RB on eosinophils was significantly higher in allergic asthmatics (43.08%, range 33.96-59.98%) than in atopic nonasthmatics (11.98%, range 6.33-27.11%, p = 0.002) and normal controls (17.70%, range 10.97-38.9%, p = 0.01). IL-17RA expression was also significantly higher in the allergic asthmatic group. No differences were observed in the intracellular expression of IL-25. The concentration of IL-25 in plasma was significantly increased in the allergic asthmatics (145 ng/ml, range 64-290 ng/ml) when compared to the normal controls (21 ng/ml, range 0-116 ng/ml, p = 0.012), but not compared to atopic nonasthmatics. There was a significant negative correlation between FEV1 % predicted and the IL-25 level in the plasma (r = -0.443, p = 0.003). Conclusions: The increased IL-25 levels in plasma and the expression of IL-17RA and IL-17RB on eosinophils in allergic asthma patients suggests that IL-25 may activate eosinophils during allergic inflammation. © 2013 S. Karger AG, Basel.
    International Archives of Allergy and Immunology 11/2013; 163(1):5-10. DOI:10.1159/000355331 · 2.43 Impact Factor
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    ABSTRACT: The OX40/OX40L interaction contributes to an optimal T cell response following allergic stimuli, and plays an important role in the maintenance and reactivation of memory T effector cells. We tested whether treatment with an OX40L monoclonal antibody (MAb) would inhibit allergen-induced responses in subjects with asthma. Twenty-eight mild, atopic asthmatic subjects were recruited for a double-blind, randomized, placebo-controlled, parallel group trial (ClinicalTrials.gov identifier NCT00983658) to compare blockade of OX40L using a humanized OX40L MAb to placebo administered intravenously in 4 doses over 3 months. Allergen inhalation challenges were carried out 56 and 113 days after the first dose of study drug. The primary outcome variable was the late phase asthmatic response. Other outcomes included the early phase asthmatic response, airway hyperresponsiveness, serum IgE levels, blood and sputum eosinophils, safety and tolerability. Treatment with OX40L MAb did not attenuate the early or late phase asthmatic responses at Days 56 or 113 compared to placebo. In the OX40L MAb treatment group, total IgE was reduced 17% from pre-dosing levels, and sputum eosinophils decreased 75% by Day 113 (both p=0.04). There was no effect of OX40L MAb on airway hyperresponsiveness or blood eosinophils. The frequency of AEs was similar in both groups. Pharmacological activity of OX40L MAb was observed by decreases in serum total IgE and airway eosinophils at 16 weeks post-dosing, but there was no effect on allergen-induced airway responses. It is possible that the treatment duration or dose of antibody was insufficient to impact the airway responses. This article is protected by copyright. All rights reserved.
    Clinical & Experimental Allergy 11/2013; DOI:10.1111/cea.12235 · 4.32 Impact Factor