Gail M Gauvreau

McMaster University, Hamilton, Ontario, Canada

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Publications (104)713.96 Total impact

  • 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. · 1.29 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.
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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. · 10.76 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.
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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).
  • 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. 06/2014; 18(7).
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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; · 54.42 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; · 3.71 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; · 4.79 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. · 3.53 Impact Factor
  • Jeremy A Scott, Gail M Gauvreau, Hartmut Grasemann
    European Respiratory Journal 02/2014; 43(2):647-8. · 6.36 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 01/2014; 15(4):6062-71. · 2.46 Impact Factor
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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. · 2.25 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; · 4.79 Impact Factor
  • European Respiratory Journal 10/2013; · 6.36 Impact Factor
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    ABSTRACT: Natural regulatory T (Treg) cells are implicated in the regulation of the inflammatory response in patients with allergic asthma. We sought to determine changes in Treg cell numbers in the airways and peripheral blood of isolated early responder (IER) versus dual responder (DR) subjects with mild allergic asthma before and after allergen challenge. Induced sputum was collected from 22 subjects with allergic asthma (10 IERs and 12 DRs) and peripheral blood collected from 8 DRs with allergic asthma at 0, 7, and 24 hours after allergen challenge. Treg cells were identified by using fluorescently labeled antibodies to CD4 and forkhead box protein 3 and enumerated by using flow cytometry. There was a significant increase in the percentage of sputum CD4(+) cells 24 hours after allergen challenge in both IERs and DRs. The percentage of sputum Treg cells significantly decreased 24 hours after challenge in DRs but not IERs. This change was significantly correlated with the magnitude of the late asthmatic response. There was also a significant increase in the absolute number of sputum CD4(+) cells and Treg cells at 24 hours in DRs only. The ratio of the number of Treg cells to CD4(+) cells at 24 hours was significantly smaller in DRs compared with that in IERs. None of the above changes were observed in peripheral blood. DRs exhibit a diminished percentage of airway Treg cells after allergen challenge that is not observed in IERs and a significantly lower ratio of Treg cells to CD4(+) cells, which might contribute to the development of the late asthmatic response.
    The Journal of allergy and clinical immunology 10/2013; · 12.05 Impact Factor
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    ABSTRACT: The allergen bronchoprovocation test is a long-standing exacerbation model of allergic asthma that can induce several clinical and pathophysiologic features of asthma in sensitized subjects. Standardized allergen challenge is primarily a research tool, and when properly conducted by qualified and experienced investigators, it is safe and highly reproducible. In combination with validated airway sampling and sensitive detection techniques, allergen challenge allows the study of several features of the physiology of mainly TH2 cell-driven asthma in relation to the kinetics of the underlying airway pathology occurring during the allergen-induced late response. Furthermore, given the small within-subject variability in allergen-induced airway responses, allergen challenge offers an adequate disease model for the evaluation of new (targeted) controller therapies for asthma in a limited number of subjects. In proof-of-efficacy studies thus far, allergen challenge showed a fair positive predicted value and an excellent negative predictive value for the actual clinical efficacy of new antiasthma therapies, underscoring its important role in early drug development. In this review we provide recommendations on challenge methods, response measurements, sample size, safety, and harmonization for future applications.
    The Journal of allergy and clinical immunology 10/2013; · 12.05 Impact Factor
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    ABSTRACT: Myeloid dendritic cells type 2 (mDC2s) are a new subtype of DCs identified in both the circulation and the lung and suggested to have a role in allergic asthma. Circulating mDC2s were enumerated in 19 healthy, 18 atopic nonasthmatic, 18 mild atopic asthmatic, and 16 moderate/severe atopic asthmatic subjects using flow cytometry. The number of circulating mDC2s was significantly lower in atopic subjects compared with healthy controls and in asthmatic subjects compared with nonasthmatic subjects. There was a trend toward lower levels of circulating mDC2s with increasing allergy and asthma severity. The largest differences were seen in moderate/severe atopic asthmatics being 430.78 ± 48.91/ml compared with healthy controls being 767.05 ± 101.64/ml (P < 0.05). Circulating mDC2s are lower in atopic and asthmatic subjects, which suggests that these cells efflux from the blood into the airways in patients with allergic disease.
    Allergy 08/2013; · 5.88 Impact Factor
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    ABSTRACT: Many asthmatic patients exhibit sputum eosinophilia associated with exacerbations. Benralizumab targets eosinophils by binding IL-5 receptor α, inducing apoptosis through antibody-dependent cell-mediated cytotoxicity. We sought to evaluate the safety of benralizumab in adults with eosinophilic asthma and its effects on eosinophil counts in airway mucosal/submucosal biopsy specimens, sputum, bone marrow, and peripheral blood. In this multicenter, double-blind, placebo-controlled phase I study, 13 subjects were randomized to single-dose intravenous placebo or 1 mg/kg benralizumab (day 0; cohort 1), and 14 subjects were randomized to 3 monthly subcutaneous doses of placebo or 100 or 200 mg of benralizumab (days 0, 28, and 56; cohort 2). Cohorts 1 and 2 were consecutive. The incidence of adverse events was similar between groups. No serious adverse events related to benralizumab occurred. In cohort 1 intravenous benralizumab produced a median decrease from baseline of 61.9% in airway mucosal eosinophil counts (day 28; placebo: +19.6%; P = .28), as well as an 18.7% decrease (day 21) in sputum and a 100% decrease (day 28) in blood counts. Eosinophils were not detectable in bone marrow of benralizumab-treated subjects (day 28, n = 4). In cohort 2 subcutaneous benralizumab demonstrated a combined (100 + 200 mg) median reduction of 95.8% in airway eosinophil counts (day 84; placebo, 46.7%; P = .06), as well as an 89.9% decrease (day 28) in sputum and a 100% decrease (day 84) in blood counts. Single-dose intravenous and multiple-dose subcutaneous benralizumab reduced eosinophil counts in airway mucosa/submucosa and sputum and suppressed eosinophil counts in bone marrow and peripheral blood. The safety profile supports further development. Additional studies are needed to assess the clinical benefit in asthmatic patients.
    The Journal of allergy and clinical immunology 07/2013; · 12.05 Impact Factor
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    ABSTRACT: Upregulation of arginase contributes to airways hyperresponsiveness (AHR) in asthma by reducing L-arginine bioavailability for the nitric oxide synthase isozymes. The product of arginase activity, L-ornithine, can be metabolized into polyamines by ornithine decarboxylase. We tested the hypothesis that increases in L-ornithine-derived polyamines contribute to AHR in mouse models of allergic airways inflammation. After measuring significantly increased polyamine levels in sputum samples from human subjects with asthma following allergen challenge, we used acute and sub-acute ovalbumin-sensitization and -challenge mouse models of allergic airways inflammation and naïve mice to investigate the relation between AHR to methacholine and polyamines in the lung. We found that spermine levels were elevated significantly in lungs from the acute model, which exhibits robust AHR, but not in the sub-acute murine model of asthma, which does not develop AHR. Intratracheal administration of spermine significantly augmented airways responsiveness to methacholine in both naïve mice and mice with subacute airways inflammation, and reduced nitrite/nitrate levels in lung homogenates, suggesting that the AHR developed as a consequence of inhibition of constitutive nitric oxide (cNO) production in the airways. Chronic inhibition of polyamine synthesis using an ornithine decarboxylase inhibitor significantly reduced polyamine levels, restored nitrite/nitrate levels to normal and abrogated the AHR to methacholine in the acute model of allergic airways inflammation. We demonstrate that spermine increases airways responsiveness to methacholine, likely through inhibition of cNO synthesis. Thus, inhibition of polyamine production may represent a new therapeutic target to treat airway obstruction in allergic asthma.
    American Journal of Respiratory Cell and Molecular Biology 06/2013; 48(6):694-702. · 4.15 Impact Factor

Publication Stats

2k Citations
713.96 Total Impact Points

Institutions

  • 1996–2014
    • McMaster University
      • • Division of Clinical Immunology and Allergy
      • • Department of Medicine
      Hamilton, Ontario, Canada
  • 2013
    • Universitair Medisch Centrum Groningen
      Groningen, Groningen, Netherlands
  • 2012–2013
    • St. Paul's Hospital
      Saskatoon, Saskatchewan, Canada
  • 2011
    • Kurume University
      • Division of Respirology, Neurology, and Rheumatology
      Куруме, Fukuoka, Japan
  • 2008
    • Saint Joseph Hospital
      Chicago, Illinois, United States
  • 2000–2008
    • St. Joseph's Healthcare Hamilton
      Hamilton, Ontario, Canada