Helen Neighbour

Safety and efficacy of an oral CCR3 antagonist in patients with asthma and eosinophilic bronchitis: a randomized, placebo-controlled clinical trial

Several chemokines, notably eotaxin, mediate the recruitment of eosinophils into tissues via the CCR3 receptor.

Rapid effect of inhaled ciclesonide in asthma: a randomized, placebo-controlled study.

BACKGROUND Ciclesonide is a novel inhaled corticosteroid for the treatment of asthma, and it is important to measure the onset of effect of this therapy on airway hyperresponsiveness (AHR), exhaled nitric oxide (NO), and levels of eosinophils in induced sputum. METHODS In a randomized, double-blind, crossover study, 21 patients with mild asthma inhaled ciclesonide 320 microg (ex-actuator) qd, ciclesonide 640 microg (ex-actuator) bid, and placebo for 7 days. Exhaled NO and AHR to adenosine monophosphate (AMP), measured as the provocative concentration of AMP producing a 20% reduction in FEV1 (PC20FEV1), were assessed after inhalation on days 1, 3 and 7. Eosinophil levels in induced sputum were also measured. RESULTS Ciclesonide 320 microg qd and 640 microg bid produced significantly greater improvements in PC20FEV1 compared with placebo on day 1 (within 2.5 h), and on days 3 and 7 (all p < 0.0001). On day 3, both ciclesonide doses significantly reduced exhaled NO levels by - 17.7 parts per billion (p < 0.0001) and - 15.4 parts per billion (p < 0.003) vs placebo, respectively. Significant reductions were maintained during the study with both ciclesonide doses (p < 0.01). A nonsignificant trend towards a decrease in eosinophil cell numbers was observed after 7 days of ciclesonide treatment, especially in patients receiving the higher dose. CONCLUSIONS A single dose of ciclesonide decreased AHR to AMP and exhaled NO within 3 h, while FEV, improved at 3 days and 7 days.

Amelioration of ovalbumin-induced allergic airway disease following Der p 1 peptide immunotherapy is not associated with induction of IL-35

In the present study, we show therapeutic amelioration of established ovalbumin (OVA)-induced allergic airway disease following house dust mite (HDM) peptide therapy. Mice were sensitized and challenged with OVA and HDM protein extract (Dermatophagoides species) to induce dual allergen sensitization and allergic airway disease. Treatment of allergic mice with peptides derived from the major allergen Der p 1 suppressed OVA-induced airway hyperresponsiveness, tissue eosinophilia, and goblet cell hyperplasia upon rechallenge with allergen. Peptide treatment also suppressed OVA-specific T-cell proliferation. Resolution of airway pathophysiology was associated with a reduction in recruitment, proliferation, and effector function of TH2 cells and decreased interleukin (IL)-17+ T cells. Furthermore, peptide immunotherapy induced the regulatory cytokine IL-10 and increased the proportion of Fox p3+ cells among those expressing IL-10. Tolerance to OVA was not associated with increased IL-35. In conclusion, our results provide in vivo evidence for the creation of a tolerogenic environment following HDM peptide immunotherapy, leading to the therapeutic amelioration of established OVA-induced allergic airway disease.

Targeted therapy of bronchitis in obstructive airway diseases.

Guidelines for the management of obstructive airway diseases do not emphasize the measurement of bronchitis to indicate appropriate treatments or monitor response to treatment. Bronchitis is the central component of airway diseases and contributes to symptoms, physiological and structural abnormalities. It can be measured directly and reliably by quantitative assay of spontaneous or induced sputum. The measurement is reproducible, valid, and responsive to treatment and to changes in disease status. Bronchitis may be eosinophilic, neutrophilic, mixed, or paucigranulocytic (eosinophils and neutrophils not elevated). Eosinophilic bronchitis is usually a Th2 driven process and therefore a sputum eosinophilia of greater than 3% usually indicates a response to treatment with corticosteroids or novel therapies directed against Th2 cytokines such as IL-4, IL-5 and IL-13. Neutrophilic bronchitis which is a non-Th2 driven disease is generally a predictor of response to antibiotics and may be a predictor to therapies targeted at pathways that lead to neutrophil recruitment such as IL-8 (eg anti-CXCR2), IL-17 (eg anti-IL17) etc. Paucigranulocytic disease may not warrant anti-inflammatory therapy. Several novel monoclonals and small molecule antagonists have been evaluated in clinical trials with variable results and several more are likely to be discovered in the near future. The success of these agents will depend on appropriate patient selection by accurate phenotyping or characterization of bronchitis.

The Allergic Rhinitis - Clinical Investigator Collaborative (AR-CIC): nasal allergen challenge protocol optimization for studying AR pathophysiology and evaluating novel therapies

BackgroundThe Nasal Allergen Challenge (NAC) model allows the study of Allergic Rhinitis (AR) pathophysiology and the proof of concept of novel therapies. The Allergic Rhinitis – Clinical Investigator Collaborative (AR-CIC) aims to optimize the protocol, ensuring reliability and repeatability of symptoms to better evaluate the therapies under investigation.Methods20 AR participants were challenged, with 4-fold increments of their respective allergens every 15 minutes, to determine the qualifying allergen concentration (QAC) at which the Total Nasal Symptom Score (TNSS) of ≥10/12 OR a Peak Nasal Inspiratory Flow (PNIF) reduction of ≥50% from baseline was achieved. At the NAC visit, the QAC was used in a single challenge and TNSS and PNIF were recorded at baseline, 15 minutes, 30 minutes, 1 hour, and hourly up to 12 hours. 10 additional ragweed allergic participants were qualified at TNSS of ≥8/12 AND ≥50% PNIF reduction; the Cumulative Allergen Challenge (CAC) of all incremental doses was used during the NAC visit. 4 non-allergic participants were challenged with the highest allergen concentration.ResultsIn the QAC study, a group qualified by only meeting PNIF criteria achieved lower TNSS than those achieving either TNSS criteria or PNIIF+TNSS (p<0.01). During the NAC visit, participants in both studies reached their peak symptoms at 15minutes followed by a gradual decline, significantly different from non-allergic participants. The “PNIF only” group experienced significantly lower TNSS than the other groups during NAC visit. QAC and CAC participants did not reach the same peak TNSS during NAC that was achieved at screening. QAC participants qualifying based on TNSS or TNSS+PNIF managed to maintain PNIF scores.ConclusionsParticipants experienced reliable symptoms of AR in both studies, using both TNSS and PNIF reduction as part of the qualifying criteria proved better for qualifying participants at screening. Phenotyping based on pattern of symptoms experienced is possible and allows the study of AR pathophysiology and can be applied in evaluation of efficacy of a novel medication. The AR-CIC aims to continue to improve the model and employ it in phase 2 and 3 clinical trials.

T cell‐mediated induction of thymic stromal lymphopoietin in differentiated human primary bronchial epithelial cells

Inhaled peptide challenge has been shown to induce T cell‐mediated, isolated late asthmatic reaction (LAR), characterized by recruitment of CD4+ T cells and increased levels of thymus and activation‐regulated chemokine (TARC; CCL17). Epithelial‐derived thymic stromal lymphopoietin (TSLP) has been shown to modulate dendritic cell function to promote TH2 responses via CCL17 production.

The contribution of histamine to the action of bradykinin in the human nasal airway

Bradykinin, 10 to 1000 micrograms given by aerosol into the nasal cavity of normal, healthy volunteers, produced a dose-related increase of nasal airway resistance. Bradykinin also reduced the minimal nasal cross-sectional area (Amin), increased albumin release into nasal lavage fluid and increased the symptoms of nasal inflammation. Pretreatment with cetirizine (10 mg orally) reduced the fall in Amin induced by bradykinin, 300 micrograms, but not by bradykinin, 100 micrograms. Pre-treatment of the subjects with the H1 histamine receptor antgonist cetirizine (10 mg, orally) or terfenadine (60 mg, orally) 3 h before bradykinin administration caused significant reduction of the bradykinin-induced increase in nasal airway resistance in the upper range of bradykinin doses (300-1000 micrograms) but not in the lower range (10-100 micrograms). Cetirizine reduced the albumin release into the nasal airway and the symptoms induced by bradykinin, 1000 micrograms. Following nasal challenge with bradykinin 300 micrograms or 1000 micrograms, no increase could be detected in the histamine content of nasal lavage fluid. Isolated human nasal cells released histamine in response to bradykinin, 33 and 100 microM, anti-IgE and calcium ionophore, A23187. We conclude that the actions of bradykinin in the human nasal airway are, in part, accounted for by the release of histamine.

Thymic stromal lymphopoietin (TSLP) secretion from human nasal epithelium is a function of TSLP genotype

Recent candidate gene and genome-wide association studies have identified “protective” associations between the single-nucleotide polymorphism (SNP) rs1837253 in the TSLP gene and risk for allergy, asthma, and airway hyperresponsiveness. The absence of linkage disequilibrium of rs1837253 with other SNPs in the region suggests it is likely a causal polymorphism for these associations, having functional consequences. We hypothesized that rs1837253 genotype would influence TSLP secretion from mucosal surfaces. We therefore evaluated the secretion of TSLP protein from primary nasal epithelial cells (NECs) of atopic and nonatopic individuals and its association with rs1837253 genotype. We found that although atopic sensitization does not affect the secretion of TSLP from NECs, there was decreased TSLP secretion in NECs obtained from heterozygous (CT; 1.8-fold) and homozygous minor allele (TT; 2.5-fold) individuals, as compared with NECs from homozygous major allele individuals (CC; P<0.05), after double-stranded RNA (dsRNA) stimulation (50 μg ml−1). Our novel results show that rs1837253 polymorphism may be directly involved in the regulation of TSLP secretion. This may help explain the protective association of this genetic variant with asthma and related traits. Identifying functional consequences of SNPs in genes with previously reported clinical associations is critical in understanding and targeting allergic inflammation.

Mechanisms of Aspirin-Intolerant Asthma: Identifying Inflammatory Pathways in the Pathogenesis of Asthma

pathway to form the leukotriene, LTA 4 . LTA 4 is an unstable compound and is rapidly metabolized to either LTB 4 or the cysteinyl leukotrienes (CysLTs). The CysLTs are leukocyte chemoattractants and bronchoconstrictors. In addition to COX and 5-LO pathways, 15-lipoxygenase catalyzes the hydroperoxidation of arachidonic acid to form 15-HPETE which is then further metabolized to form 15-HETE and the lipoxins and eoxins. Aspirin causes irreversible inhibition of COX-1 and competes directly with arachidonic acid for binding to the COX site. The proposed mechanism of AIA is the generation of increased levels of CysLTs as a result of increased levels of precursors due the inhibition of COX by aspirin. Eosinophils generate large amounts of CysLTs, and the appearance of increased levels of eosinophils in the bronchial musosa has been observed in AIA [3] . It has also previously been shown that that activated sputum eosinophils from subjects with AIA produce increased levels of CysLTs ex vivo [4] . This is the first data that define the release of arachidonic acid metabolites from blood eosinophils from well-characterized subjects with AIA. In addition, the responses of normal subjects and differing severities of asthma were studied, allowing the effect of dose of inhaled steroid to be investigated. Much attention has been paid to the biological role of 5-LO, but relatively little is known about 15-LO and its Asthma is a disease that is associated with considerable morbidity, and still has an associated mortality. Corticosteroids remain the main effective treatment for asthma, but these are associated with potentially serious side effects. Identification of inflammatory pathways in the pathogenesis of asthma allows new therapeutic targets to be proposed. There is a subset of patients with asthma who experience an exacerbation of their asthma when they take aspirin, so-called aspirin-intolerant asthma (AIA). The association between aspirin and asthma has been known since 1922 when it was first described by Widal [1] ; however, it only received widespread recognition in the 1960s when Samter and Beers [2] published the association between asthma, nasal polyps and aspirin sensitivity, subsequently referred to as Samter’s triad. The recognition of aspirin-sensitive asthma has significant implications for patient management, as patients with AIA are more likely to have more severe disease and to develop irreversible airflow obstruction. The mechanism of AIA is due to effects on the metabolism of arachidonic acid. Arachidonic acid is a component of cell walls and is released by the action of cytosolic phospholipase A 2 . Arachidonic acid can then be metabolized through the cyclooxygenase (COX) pathway to form prostanoids or through the 5-liopoxygenase (5-LO) Published online: November 16, 2013

Relationship between sputum eosinophilia and sinus disease in patients with eosinophilic bronchitis.

Background Sinus disease is commonly seen in patients with asthma, and several studies have been published describing the relationship between sinus disease and the inflammation seen in the sputum of asthmatic subjects. In this article, we expand on this knowledge by studying patients with eosinophilic bronchitis with and without asthma. Methods We describe the relationship between the severity of sinus disease determined by the Lund-Mackay score and sputum eosinophilia. Comparisons with blood eosinophil and total immunoglobulin (IgE) measurements are made. Results We have shown that the severity of sinus disease is positively correlated with sputum eosinophil counts, and the site of sinus disease affected the level of eosinophilia. There was a positive correlation between sputum eosinophils and blood eosinophils, but there was no relationship with blood total IgE levels. Conclusions We have confirmed that there is a link between upper and lower airway inflammation and that this is not limited to patients with asthma. The process is associated with systemic inflammation as evidenced by increased blood eosinophils but appears to be independent of IgE.