MyLinh Duong

Effects of Interleukin-13 Blockade on Allergen-induced Airway Responses in Mild Atopic Asthma

RATIONALE Extensive evidence in animal models supports a role for IL-13 in the pathobiology of asthma. IMA-638 and IMA-026 are fully humanized IgG(1) antibodies that bind to different epitopes and neutralize IL-13 bioactivity. OBJECTIVES We hypothesized that anti-IL-13 treatment would inhibit allergen-induced late-phase asthmatic responses, airway hyperresponsiveness, and inflammation in subjects with asthma. METHODS Fifty-six subjects with mild, atopic asthma were recruited for two double-blind, randomized, placebo-controlled, parallel group trials to compare IMA-638 and IMA-026 IL-13 antibody treatments with placebo treatment. Drug was administered on Days 1 and 8, and allergen challenges were performed on Days 14 and 35. The primary outcome variable was the late-phase area under the curve (AUC), and secondary outcome variables were the early- and late-phase maximum percent fall in FEV(1), early AUC, allergen-induced shift in airway hyperresponsiveness, and sputum eosinophils. MEASUREMENTS AND MAIN RESULTS The treatment difference with IMA-638 on Day 14 was -19.1 FEV(1) × hour (95% confidence interval: -36.2, -1.9) for the allergen-induced early AUC and -23.8 FEV(1) × hour (95% confidence interval: -46.4, -1.2) for the late AUC (both P < 0.05), but this effect was lost by Day 35. Treatment with IMA-026 did not attenuate the asthmatic responses on Day 14 or Day 35. There was no effect of either antibody on allergen-induced airway hyperresponsiveness or sputum eosinophils. The frequency of adverse events after administration of the IL-13 antibodies was similar to placebo. CONCLUSIONS IL-13 has a role in allergen-induced airway responses in humans. Further study is required to determine whether anti-IL-13 monoclonal antibodies will be beneficial clinically.

Antisense Therapy against CCR3 and the Common Beta Chain Attenuates Allergen-induced Eosinophilic Responses

RATIONALE The drug product TPI ASM8 contains two modified phosphorothioate antisense oligonucleotides designed to inhibit allergic inflammation by down-regulating human CCR3 and the common beta chain (beta(c)) of IL-3, IL-5, and granulocyte-macrophage colony-stimulating factor receptors. OBJECTIVES This study examined the effects of inhaled TPI ASM8 on sputum cellular influx, CCR3 and beta(c) mRNA and protein levels, and the airway physiologic response after inhaled allergen. METHODS Seventeen subjects with mild atopic asthma were randomized in a crossover study to inhale 1,500 microg TPI ASM8 or placebo by nebulizer, once daily for 4 days. On Day 3, subjects underwent allergen inhalation challenge. Sputum samples were collected before and after allergen. CCR3 and beta(c) protein levels were measured by flow cytometry, mRNA was measured using real-time quantitative polymerase chain reaction, and the FEV1 was measured over 7 hours after challenge. MEASUREMENTS AND MAIN RESULTS Compared with placebo, TPI ASM8 inhibited sputum eosinophil influx by 46% (P = 0.02) and blunted the increase in total cells (63%) after allergen challenge. TPI ASM8 significantly reduced the early asthmatic response (P = 0.04) with a trend for the late asthmatic response (P = 0.08). The allergen-induced (Day 2 to Day 3) levels of beta(c) mRNA and CCR3 mRNA in sputum-derived cells were inhibited by TPI ASM8 (P = 0.039 and P = 0.054, respectively), with no significant effects on the cell surface protein expression of CCR3 and beta(c) (P > 0.05). No serious adverse events were reported. CONCLUSIONS TPI ASM8 attenuates the allergen-induced increase in target gene mRNA and airway responses in subjects with mild asthma. Clinical trial registered with www.clinicaltrials.gov (NCT 00264966).

Roflumilast attenuates allergen-induced inflammation in mild asthmatic subjects

BackgroundPhosphodiesterase 4 (PDE4) inhibitors increase intracellular cyclic adenosine monophosphate (cAMP), leading to regulation of inflammatory cell functions. Roflumilast is a potent and targeted PDE4 inhibitor. The objective of this study was to evaluate the effects of roflumilast on bronchoconstriction, airway hyperresponsiveness (AHR), and airway inflammation in mild asthmatic patients undergoing allergen inhalation challenge.Methods25 subjects with mild allergic asthma were randomized to oral roflumilast 500 mcg or placebo, once daily for 14 days in a double-blind, placebo-controlled, crossover study. Allergen challenge was performed on Day 14, and FEV1 was measured until 7 h post challenge. Methacholine challenge was performed on Days 1 (pre-dose), 13 (24 h pre-allergen), and 15 (24 h post-allergen), and sputum induction was performed on Days 1, 13, 14 (7 h post-allergen), and 15.ResultsRoflumilast inhibited the allergen-induced late phase response compared to placebo; maximum % fall in FEV1 (p = 0.02) and the area under the curve (p = 0.01). Roflumilast had a more impressive effect inhibiting allergen-induced sputum eosinophils, neutrophils, and eosinophil cationic protein (ECP) at 7 h post-allergen (all p = 0.02), and sputum neutrophils (p = 0.04), ECP (p = 0.02), neutrophil elastase (p = 0.0001) and AHR (p = 0.004) at 24 h post-allergen.ConclusionsThis study demonstrates a protective effect of roflumilast on allergen-induced airway inflammation. The observed attenuation of sputum eosinophils and neutrophils demonstrates the anti-inflammatory properties of PDE4 inhibition and supports the roles of both cell types in the development of late phase bronchoconstriction and AHR.Trial RegistrationClinicalTrials.gov: NCT01365533

Circulating myeloid and plasmacytoid dendritic cells after allergen inhalation in asthmatic subjects

Background: Dendritic cells are key contributors to initiation and maintenance of T‐cell immunity to inhaled allergen. The purpose of this study was to enumerate the changes in peripheral blood myeloid (mDCs) and plasmacytoid dendritic cells (pDCs), the DCs expressing chemokine receptor 6 (CCR6) and chemokine receptor 7 (CCR7), following diluent and allergen inhalation in asthmatic subjects.

Global differences in lung function by region (PURE): an international, community-based prospective study

BACKGROUND Despite the rising burden of chronic respiratory diseases, global data for lung function are not available. We investigated global variation in lung function in healthy populations by region to establish whether regional factors contribute to lung function. METHODS In an international, community-based prospective study, we enrolled individuals from communities in 17 countries between Jan 1, 2005, and Dec 31, 2009 (except for in Karnataka, India, where enrolment began on Jan 1, 2003). Trained local staff obtained data from participants with interview-based questionnaires, measured weight and height, and recorded forced expiratory volume in 1 s (FEV₁) and forced vital capacity (FVC). We analysed data from participants 130-190 cm tall and aged 34-80 years who had a 5 pack-year smoking history or less, who were not affected by specified disorders and were not pregnant, and for whom we had at least two FEV₁ and FVC measurements that did not vary by more than 200 mL. We divided the countries into seven socioeconomic and geographical regions: south Asia (India, Bangladesh, and Pakistan), east Asia (China), southeast Asia (Malaysia), sub-Saharan Africa (South Africa and Zimbabwe), South America (Argentina, Brazil, Colombia, and Chile), the Middle East (Iran, United Arab Emirates, and Turkey), and North America or Europe (Canada, Sweden, and Poland). Data were analysed with non-linear regression to model height, age, sex, and region. FINDINGS 153,996 individuals were enrolled from 628 communities. Data from 38,517 asymptomatic, healthy non-smokers (25,614 women; 12,903 men) were analysed. For all regions, lung function increased with height non-linearly, decreased with age, and was proportionately higher in men than women. The quantitative effect of height, age, and sex on lung function differed by region. Compared with North America or Europe, FEV1 adjusted for height, age, and sex was 31·3% (95% CI 30·8-31·8%) lower in south Asia, 24·2% (23·5-24·9%) lower in southeast Asia, 12·8% (12·4-13·4%) lower in east Asia, 20·9% (19·9-22·0%) lower in sub-Saharan Africa, 5·7% (5·1-6·4%) lower in South America, and 11·2% (10·6-11·8%) lower in the Middle East. We recorded similar but larger differences in FVC. The differences were not accounted for by variation in weight, urban versus rural location, and education level between regions. INTERPRETATION Lung function differs substantially between regions of the world. These large differences are not explained by factors investigated in this study; the contribution of socioeconomic, genetic, and environmental factors and their interactions with lung function and lung health need further clarification. FUNDING Full funding sources listed at end of the paper (see Acknowledgments).

Anti-inflammatory effects of once daily low dose inhaled ciclesonide in mild to moderate asthmatic patients.

Background:  Ciclesonide exhibits clinical efficacy at 160 μg (ex‐actuator) once daily but the anti‐inflammatory effects at this dose are not known. We wished to know whether 4 weeks therapy with ciclesonide pMDI 160 μg once daily in the morning exhibited significant anti‐inflammatory effects.

An evaluation of peripheral blood eosinophil/basophil progenitors following nasal allergen challenge in patients with allergic rhinitis

Objective To evaluate the effect of a single nasal allergen challenge on peripheral blood eosinophil/basophil (Eo/B) progenitor cells and induced sputum eosinophil counts in subjects with allergic rhinitis.

Effects of inhaled ciclesonide on circulating T-helper type 1/T-helper type 2 cells in atopic asthmatics after allergen challenge

Background The predominance of T‐helper type 2 (Th2) lymphocytes is thought to underlie the pathogenesis of asthma. Allergen inhalation challenge in atopic asthmatic subjects is associated with decreased interferon‐γ (IFN‐γ) positive CD4+ and CD8+ lymphocytes in peripheral blood and induced sputum.

The effects of montelukast on tissue inflammatory and bone marrow responses in murine experimental allergic rhinitis: interaction with interleukin‐5 deficiency

The cysteinyl leukotrienes (cysLTs) are potent lipid mediators in allergic disease, acting through the receptors, cysLT1R and cysLTR2, and are produced by eosinophils derived from eosinophil/basophil (Eo/B) bone marrow (BM) progenitors. We have demonstrated the suppressive effects of either interleukin‐5 (IL‐5) deficiency or montelukast on eosinophil recruitment in murine allergic rhinitis, but neither of them fully abrogated the symptoms caused by residual inflammation and cytokine redundancy in eliciting BM Eo/B responses. We hypothesized that IL‐5 deficiency and montelukast act synergistically to suppress tissue inflammatory and BM responses. Our objective was to investigate the effects of the cysLT1R antagonist, montelukast, on in vivo tissue inflammatory and BM responses in murine experimental allergic rhinitis with or without IL‐5 deficiency. Three groups of age‐matched BALB/c mice with or without IL‐5 deficiency were tested: controls (ovalbumin sensitization and challenge, placebo treatment) and two montelukast‐treated groups (2·5 mg/kg or 5 mg/kg). Nasal symptoms, BM and nasal mucosal eosinophils, basophils, and BM Eo/B colony‐forming units (CFU) were evaluated. Montelukast decreased nasal symptoms in a dose‐dependent manner, and significantly decreased the number of eosinophils in both BM and nasal tissue in IL‐5‐replete mice compared to controls. In IL‐5‐deficient mice, in which eosinophilia was absent, montelukast significantly decreased both nasal symptoms and basophils in BM and nasal mucosal tissue, and lowered IL‐5‐responsive Eo/B‐CFU ex vivo, compared to controls. The addition of cysLT1R blockade to IL‐5 deficiency more fully attenuates symptoms and upper airway inflammation than either factor alone, providing evidence of systemic, BM mechanisms in allergic rhinitis.

Effects of bidi smoking on all-cause mortality and cardiorespiratory outcomes in men from south Asia: an observational community-based substudy of the Prospective Urban Rural Epidemiology Study (PURE)

BACKGROUND Bidis are minimally regulated, inexpensive, hand-rolled tobacco products smoked in south Asia. We examined the effects of bidi smoking on baseline respiratory impairment, and prospectively collected data for all-cause mortality and cardiorespiratory events in men from this region. METHODS This substudy of the international, community-based Prospective Urban Rural Epidemiology (PURE) study was done in seven centres in India, Pakistan, and Bangladesh. Men aged 35-70 years completed spirometry testing and standardised questionnaires at baseline and were followed up yearly. We used multilevel regression to compare cross-sectional baseline cardiorespiratory symptoms, spirometry measurements, and follow-up events (all-cause mortality, cardiovascular events, respiratory events) adjusted for socioeconomic status and baseline risk factors between non-smokers, light smokers of bidis or cigarettes (≤10 pack-years), heavy smokers of cigarettes only (>10 pack-years), and heavy smokers of bidis (>10 pack-years). FINDINGS 14 919 men from 158 communities were included in this substudy (8438 non-smokers, 3321 light smokers, 959 heavy cigarette smokers, and 2201 heavy bidi smokers). Mean duration of follow-up was 5·6 years (range 1-13). The adjusted prevalence of self-reported chronic wheeze, cough or sputum, dyspnoea, and chest pain at baseline increased across the categories of non-smokers, light smokers, heavy cigarette smokers, and heavy bidi smokers (p<0·0001 for association). Adjusted cross-sectional age-related changes in forced expiratory volume in 1 s (FEV1) and FEV1/forced vital capacity (FVC) ratio were larger for heavy bidi smokers than for the other smoking categories. Hazard ratios (relative to non-smokers) showed increasing hazards for all-cause mortality (light smokers 1·28 [95% CI 1·02-1·62], heavy cigarette smokers 1·59 [1·13-2·24], heavy bidi smokers 1·56 [1·22-1·98]), cardiovascular events (1·45 [1·13-1·84], 1·47 [1·05-2·06], 1·55 [1·17-2·06], respectively) and respiratory events (1·30 [0·91-1·85], 1·21 [0·70-2·07], 1·73 [1·23-2·45], respectively) across the smoking categories. INTERPRETATION Bidi smoking is associated with severe baseline respiratory impairment, all-cause mortality, and cardiorespiratory outcomes. Stricter controls and regulation of bidis are needed to reduce the tobacco-related disease burden in south Asia. FUNDING Population Health Research Institute, Canadian Institutes of Health Research, and Heart and Stroke Foundation of Ontario.