ABSTRACT
BACKGROUND: CCR3 is the cognate receptor for major human eosinophil chemoattractants from the eotaxin family of proteins that are elevated in asthma and correlate with disease severity. OBJECTIVE: This proof-of-mechanism study examined the effect of AXP1275, an oral, small-molecule inhibitor of CCR3, on airway responses to inhaled allergen challenge. METHODS: Twenty-one subjects with mild atopic asthma and documented early and late asthmatic responses to an inhaled aeroallergen completed a randomized double-blind cross-over study to compare early and late allergen-induced asthmatic responses, methacholine PC20 , blood and sputum eosinophils and exhaled nitric oxide after 2 weeks of treatment with once-daily doses of AXP1275 (50 mg) or placebo. RESULTS: There was a significant increase in methacholine PC20 after 12 days of AXP1275 treatment compared to placebo (increase of 0.92 doubling doses versus 0.17 doubling doses, P = .01), but this protection was lost post-allergen challenge. There was no effect of AXP1275 on allergen-induced late asthmatic responses, or eosinophils in blood and sputum. The early asthmatic response and exhaled nitric oxide levels were slightly lower with AXP1275, but this did not reach statistical significance. The number of subjects who experienced treatment-emergent adverse events while receiving AXP1275 was comparable placebo. CONCLUSIONS & CLINICAL RELEVANCE: AXP1275 50 mg administered daily was safe and well tolerated, and there was no difference in the type, severity or frequency of treatment-emergent adverse events in subjects while receiving AXP1275 compared to placebo. AXP1275 increased the methacholine PC20 ; however, the low and variable exposure to APX1275 over a short treatment period may have contributed to poor efficacy on other outcomes.
Subject(s)
Anti-Asthmatic Agents/therapeutic use , Asthma/drug therapy , Organic Chemicals/therapeutic use , Receptors, CCR3/antagonists & inhibitors , Adult , Allergens/adverse effects , Allergens/immunology , Bronchial Provocation Tests , Cross-Over Studies , Double-Blind Method , Female , Humans , MaleABSTRACT
BACKGROUND: In mouse models of allergic asthma, exposure to different allergens can trigger distinct inflammatory subtypes in the airways. We investigated whether this observation extends to humans. METHODS: We compared the frequency of sputum inflammatory subtypes between mild allergic asthma subjects (n = 129) exposed to different allergens in inhalation challenge tests. These tests were performed using a standardized protocol as part of clinical trials of experimental treatments for asthma, prior to drug randomization. Five allergen types were represented: the house dust mites Dermatophagoides pteronyssinus and Dermatophagoides farinae, ragweed, grass, and cat. RESULTS: Of 118 individuals with a sputum sample collected before allergen challenge (baseline), 45 (38%) had paucigranulocytic, 51 (43%) eosinophilic, 11 (9%) neutrophilic, and 11 (9%) mixed granulocytic sputum. Of note, most individuals with baseline paucigranulocytic sputum developed eosinophilic (48%) or mixed granulocytic (43%) sputum 7 hours after allergen challenge, highlighting the dynamic nature of sputum inflammatory subtype in asthma. Overall, there was no difference in the frequency of sputum inflammatory subtypes following challenge with different allergen types. Similar results were observed at 24 hours after allergen challenge. CONCLUSIONS: Unlike reported in mice, in humans the sputum inflammatory subtype observed after an allergen-induced asthma exacerbation is unlikely to be influenced by the type of allergen used.
Subject(s)
Allergens/immunology , Hypersensitivity/diagnosis , Hypersensitivity/immunology , Sputum/cytology , Sputum/immunology , Allergens/administration & dosage , Animals , Asthma/diagnosis , Asthma/immunology , Bronchial Provocation Tests , Granulocytes/immunology , Granulocytes/metabolism , Humans , Immunization , Immunoglobulin E/immunology , Mice , Retrospective Studies , Skin TestsABSTRACT
BACKGROUND: Glucagon-like peptide-1 (GLP-1) and its receptor are part of the incretin family of hormones that regulate glucose metabolism. GLP-1 also has immune modulatory roles. OBJECTIVES: To measure the expression of the GLP-1 receptor (GLP-1R) on eosinophils and neutrophils in normal and asthmatic subjects and evaluate effects of a GLP-1 analog on eosinophil function. METHODS: Peripheral blood samples were taken from 10 normal and 10 allergic asthmatic subjects. GLP-1R expression was measured on eosinophils and neutrophils. Subsequently, the asthmatic subjects underwent allergen and diluent inhalation challenges, and GLP-1R expression was measured. Purified eosinophils, collected from mild asthmatic subjects, were stimulated with lipopolysaccharide (LPS) and a GLP-1 analog to evaluate eosinophil cell activation markers CD11b and CD69 and cytokine (IL-4, IL-5, IL-8 and IL-13) production. RESULTS: Glucagon-like peptide-1 receptor is expressed on human eosinophils and neutrophils. Eosinophil, but not neutrophil, expression of GLP-1R is significantly higher in normal controls compared to allergic asthmatics. The expression of GLP-1R did not change on either eosinophils or neutrophils following allergen challenge. A GLP-1 analog significantly decreased the expression of eosinophil-surface activation markers following LPS stimulation and decreased eosinophil production of IL-4, IL-8 and IL-13, but not IL-5. CONCLUSION AND CLINICAL RELEVANCE: Glucagon-like peptide-1 receptor is expressed on human eosinophils and neutrophils. A GLP-1 analog attenuates LPS-stimulated eosinophil activation. GLP-1 agonists may have additional adjunctive indications in treating persons with concomitant type 2 diabetes mellitus and asthma.
Subject(s)
Eosinophils/immunology , Eosinophils/metabolism , Gene Expression , Glucagon-Like Peptide-1 Receptor/genetics , Immunomodulation/genetics , Adult , Allergens/administration & dosage , Allergens/immunology , Asthma/diagnosis , Asthma/genetics , Asthma/immunology , Asthma/metabolism , Bronchial Provocation Tests , Female , Humans , Male , Methacholine Chloride/administration & dosage , Middle Aged , Respiratory Function Tests , Young AdultABSTRACT
BACKGROUND: The cysteinyl leukotrienes (cysLTs) play a key role in the pathophysiology of asthma. In addition to functioning as potent bronchoconstrictors, cysLTs contribute to airway inflammation through eosinophil and neutrophil chemotaxis, plasma exudation, and mucus secretion. We tested the activity of the dual cysLT1/2 antagonist, ONO-6950, against allergen-induced airway responses. METHODS: Subjects with documented allergen-induced early (EAR) and late asthmatic response (LAR) were randomized in a three-way crossover study to receive ONO-6950 (200 mg) or montelukast (10 mg) or placebo q.d. on days 1-8 of the three treatment periods. Allergen was inhaled on day 7 two hours postdose, and forced expiratory volume in 1 s (FEV1 ) was measured for 7 h following challenge. Sputum eosinophils and airway hyperresponsiveness were measured before and after allergen challenge. The primary outcome was the effect of ONO-6950 vs placebo on the EAR and LAR. RESULTS: Twenty-five nonsmoking subjects with mild allergic asthma were enrolled and 20 subjects completed all three treatment periods per protocol. ONO-6950 was well tolerated. Compared to placebo, ONO-6950 significantly attenuated the maximum % fall in FEV1 and area under the %FEV1 /time curve during the EAR and LAR asthmatic responses (P < 0.05) and allergen-induced sputum eosinophils. There were no significant differences between ONO-6950 and montelukast. CONCLUSIONS: Attenuation of EAR, LAR, and airway inflammation is consistent with cysLT1 blockade. Whether dual cysLT1/2 antagonism offers additional benefit for treatment of asthma requires further study.
Subject(s)
Allergens/immunology , Asthma/drug therapy , Asthma/immunology , Leukotriene Antagonists/therapeutic use , Receptors, Leukotriene/metabolism , Adult , Asthma/diagnosis , Asthma/metabolism , Butyrates/pharmacology , Butyrates/therapeutic use , Exhalation , Female , Humans , Indoles/pharmacology , Indoles/therapeutic use , Leukotriene Antagonists/pharmacology , Male , Nitric Oxide/metabolism , Respiratory Function Tests , Sputum/cytology , Treatment Outcome , Young AdultABSTRACT
OX40-OX40L interactions and thymic stromal lymphopoietin (TSLP) are important in the induction and maintenance of Th2 responses in allergic disease, whereas T regulatory cells (Treg) have been shown to suppress pro-inflammatory Th2 responses. Both OX40L and TSLP have been implicated in the negative regulation of Treg. The effect of anti-asthma therapies on Treg is not well known. Our aim was to assess the effects of two monoclonal antibody therapies (anti-OX40L and anti-TSLP) on Treg frequency using a human model of allergic asthma. We hypothesized that the anti-inflammatory effects of these therapies would result in an increase in circulating Treg (CD4(+) CD25(+) CD127(low) Foxp3(+) cells) frequency. We measured Treg using flow cytometry, and our results showed that neither allergen challenge nor monoclonal antibody therapy altered circulating Treg frequency. These data highlight the need for assessment of airway Treg and for a more complete understanding of Treg biology so as to develop pharmacologics/biologics that modulate Treg for asthma therapy.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Asthma/drug therapy , Asthma/immunology , CD4 Lymphocyte Count , Cytokines/antagonists & inhibitors , OX40 Ligand/antagonists & inhibitors , T-Lymphocytes, Regulatory/immunology , Adult , Antibodies, Monoclonal/pharmacology , Asthma/physiopathology , Female , Forced Expiratory Volume , Humans , Immunophenotyping , Male , Middle Aged , T-Lymphocytes, Regulatory/metabolism , Treatment Outcome , Young Adult , Thymic Stromal LymphopoietinABSTRACT
BACKGROUND: 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. OBJECTIVE: We tested whether treatment with an anti-OX40L monoclonal antibody (MAb) would inhibit allergen-induced responses in subjects with asthma. METHODS: 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 anti-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. RESULTS: Treatment with anti-OX40L MAb did not attenuate the early- or late-phase asthmatic responses at days 56 or 113 compared with placebo. In the anti-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 anti-OX40L MAb on airway hyperresponsiveness or blood eosinophils. The frequency of AEs was similar in both groups. CONCLUSION AND CLINICAL RELEVANCE: Pharmacological activity of anti-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.
Subject(s)
Allergens/immunology , Anti-Asthmatic Agents/therapeutic use , Antibodies, Monoclonal/therapeutic use , Asthma/drug therapy , Asthma/immunology , CD40 Ligand/antagonists & inhibitors , Adult , Anti-Asthmatic Agents/adverse effects , Anti-Asthmatic Agents/pharmacology , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/pharmacology , Asthma/metabolism , CD40 Antigens/metabolism , CD40 Ligand/metabolism , Dendritic Cells/immunology , Eosinophils , Female , Forced Expiratory Volume/drug effects , Humans , Immunoglobulin E/blood , Immunoglobulin E/immunology , Leukocyte Count , Male , Middle Aged , Signal Transduction/drug effects , T-Lymphocytes/immunology , Time Factors , Treatment Outcome , Young AdultABSTRACT
BACKGROUND: Patients with severe refractory asthma have not achieved asthma control, even with high doses of ICS, usually in combination with LABAs and other maintenance treatments. OBJECTIVE: The most promising approaches currently under investigation are those which reduce airway eosinophils in patients with severe refractory asthma and a persisting airway eosinophilia. RESULTS: Monoclonal antibodies against IL-5 have been shown to improve lung function, improve asthma control, reduce exacerbation risk and allow reduction or elimination of maintenance oral corticosteroids in this subset of patients. Bronchial thermoplasty may provide benefit in improving control and reducing exacerbations in selected patients. The addition of the muscarinic antagonist, tiotropium also improves airflow obstruction, but its benefit on exacerbation risk is not yet established. Other developments being evaluated in severe refractory asthma are CXCR2 antagonists in patients with a persisting neutrophilic airway inflammation, and CRTh2 antagonists, both of which are small molecule antagonists, and hMabs against IL4 and IL-13. Finally, other approaches to reduce receptor numbers, using inhaled anti-sense, has shown to reduce allergen-induced airway eosinophilia, and combining different anti-sense against different targets may become a feasible treatment option. CONCLUSIONS: A variety of new treatment options are being investigated to help improve overall asthma control in patients with severe refractory asthma. These include medications to optimize lung function; bronchial thermoplasty to reduce airway smooth muscle in central airways; and those which target specific inflammatory cells or receptors of inflammatory mediators. CLINICAL RELEVANCE: Patients with severe refractory asthma have the greatest unmet treatment needs to improve asthma control and reduce exacerbation risk. New treatment approaches have been identified which will benefit subsets of these patients. Phenotyping patients is necessary to select those likely to benefit.
Subject(s)
Asthma/therapy , Anti-Asthmatic Agents/therapeutic use , Bronchodilator Agents/therapeutic use , Humans , Hyperthermia, Induced , Inflammation/therapy , Severity of Illness IndexABSTRACT
BACKGROUND: TPI ASM8 contains two modified phosphorothioate antisense oligonucleotides (AON), one targeting the common beta chain (ßc) of the IL-3/IL-5/GM-CSF receptors and the other targeting the chemokine receptor CCR3. Inhalation of TPI ASM8 significantly improves lung function and sputum eosinophilia after allergen inhalation challenge in asthmatics. OBJECTIVE: This study assessed whether TPI ASM8 reduces airway levels of haemopoietic progenitor cells. METHODS: This open-label study was conducted in 14 stable, allergic mild asthmatic subjects with early- and late-phase allergen-induced bronchoconstriction. Subjects underwent allergen challenges after 4-day treatment with placebo, 4 mg b.i.d. and 8 mg o.d. of TPI ASM8. Sputum was induced before, 7 and 24 h after allergen challenges for progenitor measurements. Treatments were separated by 2-3 weeks. RESULTS: TPI ASM8 reduced allergen-induced sputum eosinophils, and the early and late asthmatic responses (P<0.05). TPI ASM8 also reduced the number of CD34(+) CCR3(+) cells (P=0.004) and CD34(+) IL-5Rα(+) cells (P=0.016), and the proportion of CD34(+) cells expressing IL-5Rα (P=0.036). CONCLUSIONS AND CLINICAL RELEVANCE: TPI ASM8 was safe and well tolerated. The results of this study demonstrate blocking of CCR3 and ßc expression by TPI ASM8 significantly inhibits the accumulation of eosinophils and eosinophil progenitors in the airways after allergen challenge. Inhibition of airway progenitor cell accumulation presents a novel therapeutic target.
Subject(s)
Allergens/immunology , Asthma/drug therapy , Asthma/immunology , Eosinophils/immunology , Granulocyte Precursor Cells/immunology , Oligonucleotides, Antisense/therapeutic use , Phosphorothioate Oligonucleotides/therapeutic use , Adult , Allergens/administration & dosage , Antigens, CD34/metabolism , Bronchial Provocation Tests , Eosinophils/metabolism , Female , Granulocyte Precursor Cells/drug effects , Granulocyte Precursor Cells/metabolism , Humans , Immunophenotyping , Male , Middle Aged , Oligonucleotides, Antisense/adverse effects , Phosphorothioate Oligonucleotides/adverse effects , Sputum/cytology , Sputum/immunology , Young AdultABSTRACT
BACKGROUND: Smoking asthmatics experience more severe symptoms, require more rescue medication and have more asthma-related hospitalizations than non-smoking asthmatics. However, studies in mice suggest that mainstream cigarette smoke may reduce airway inflammation and may attenuate airway hyperresponsiveness. A comparison of allergen-induced airway inflammatory responses of smoking and non-smoking atopic asthmatics has not been examined previously. OBJECTIVES: To determine whether allergen-induced airway responses and inflammatory profiles are attenuated in smoking when compared with non-smoking mild allergic asthmatic subjects. METHODS: Allergen inhalation challenges were performed in 13 smoking and 19 non-smoking mild allergic asthmatic subjects. The forced expired volume in 1 s (FEV(1) ) was measured up to 7 h after allergen inhalation. Methacholine airway responsiveness was measured before and at 24 h after allergen and sputum was induced before and at 7 and 24 h after allergen. RESULTS: Both the smoking and non-smoking groups developed similar allergen-induced falls in FEV(1) during the early and late asthmatic responses and similar increases in allergen-induced airway eosinophils. The mean maximum fall in FEV(1) during the late response was 16.3 ± 4.3% in non-smokers and 12.9 ± 7.2% in smokers. The smoking asthmatics, however, did not develop allergen-induced methacholine airway hyperresponsiveness, whereas the non-smoking controls developed a 1.18 doubling dose shift in methacholine PC(20) (P < 0.05). CONCLUSIONS AND CLINICAL RELEVANCE: Mild allergic asthmatic subjects, who were current smokers with a mean 6-year pack history, develop allergen-induced eosinophilic airway inflammation and late responses, similar in magnitude to non-smoking asthmatics, but do not develop methacholine airway hyperresponsiveness associated with the allergen-induced airway eosinophilia.
Subject(s)
Allergens/adverse effects , Asthma/pathology , Methacholine Chloride/adverse effects , Smoking , Administration, Inhalation , Adolescent , Adult , Allergens/administration & dosage , Asthma/immunology , Cotinine/urine , Humans , Methacholine Chloride/administration & dosage , Middle Aged , Sputum/cytology , Sputum/immunology , Young AdultABSTRACT
BACKGROUND: TPI ASM8 contains two modified antisense oligonucleotides (AON) targeting the beta subunit (ß(c) ) of the IL-3, IL-5, GM-CSF receptors and the chemokine receptor CCR3. A previous study suggested that TPI ASM8 had broader effects than just inhibition of eosinophils in asthmatics. OBJECTIVE: We assessed whether TPI ASM8 caused a dose-dependent attenuation in the inflammatory and physiological changes after inhaled allergen challenge (AIC). METHODS: This single-center, open-label, stepwise-ascending dose study was conducted in fourteen stable, mild allergic asthmatics. Following placebo AIC, subjects underwent AIC after 4 days treatment with 1, 2, and 4 mg BID and finally 8 mg once daily (OD) of TPI ASM8, inhaled via the I-Neb™ nebuliser. Treatments were separated by 2-3-week washout periods. RESULTS: TPI ASM8 was safe and well tolerated at all doses. TPI ASM8 8 mg OD reduced eosinophils in sputum after AIC (by 60.9% at 7 h and 68.4% at 24 h post-AIC, P=0.016 and P=0.007, respectively). Additionally, TPI ASM8 8 mg OD significantly attenuated the early and late airway responses as shown by the reduction in the area under the curve by 45% (P=0.016) and 59%, (P=0.0015), respectively, the increase in eosinophil cationic protein (ECP) by up to 57% (P=0.021), and airway responsiveness to methacholine by more than 1 doubling dose (P=0.012). A dose-response relationship was noted, and efficacy was maintained with once per day administration. CONCLUSIONS: TPI ASM8 attenuated a broad range of inflammatory and physiological changes after AIC, suggesting that CCR3, IL-3, and GM-CSF also are important targets for the management of asthma.
Subject(s)
Allergens/immunology , Anti-Asthmatic Agents/therapeutic use , Asthma/drug therapy , Asthma/immunology , Phosphorothioate Oligonucleotides/therapeutic use , Adolescent , Adult , Allergens/administration & dosage , Anti-Asthmatic Agents/administration & dosage , Anti-Asthmatic Agents/adverse effects , Anti-Asthmatic Agents/pharmacokinetics , Asthma/genetics , Cytokine Receptor Common beta Subunit/genetics , Dose-Response Relationship, Drug , Female , Gene Expression Regulation/drug effects , Humans , Male , Phosphorothioate Oligonucleotides/administration & dosage , Phosphorothioate Oligonucleotides/adverse effects , Phosphorothioate Oligonucleotides/pharmacokinetics , RNA, Messenger/genetics , Receptors, CCR3/genetics , Respiratory Hypersensitivity/drug therapy , Respiratory Hypersensitivity/immunology , Sputum/immunology , Young AdultABSTRACT
BACKGROUND: Allergen inhalation causes early and late bronchoconstrictor responses, airway hyperresponsiveness and airway inflammation in allergic asthmatics. The role of airway inflammatory cells in causing allergen-induced bronchoconstriction and airway hyperresponsiveness is controversial. The objective of this study was to examine the relationships between allergen-induced increases in airway inflammatory cells, early and late bronchoconstrictor responses and methacholine airway hyperresponsiveness. METHODS: Allergen inhalation challenge was conducted in 50 allergic asthmatics. Changes in the forced expired volume in 1 s (FEV(1%) ) were followed for 7 h, induced sputum was obtained at 7 and 24 h, and the provocative concentration of methacholine causing a 20% fall in FEV(1) (MCh PC(20) ) was measured at 24 h. RESULTS: There was a significant negative correlation between the baseline methacholine PC(20) and baseline sputum eosinophils (r = -0.512, P = 0.0001). Allergen-induced changes in methacholine PC(20) were also significantly negatively correlated to allergen-induced change in sputum eosinophils at 24 h (r = -0.434, P = 0.002), but not to changes in any other inflammatory cells. There were no significant correlations between sputum eosinophils or other inflammatory cells and the allergen-induced early or late asthmatic responses. CONCLUSION: Allergen-induced increases in airway eosinophils in asthmatic dual responders may contribute to allergen-induced changes in methacholine PC(20) , but not the late asthmatic responses.
Subject(s)
Asthma/pathology , Inflammation/pathology , Sputum/immunology , Allergens/pharmacology , Bronchoconstrictor Agents , Eosinophils/immunology , Humans , Methacholine Chloride/pharmacologyABSTRACT
Haemopoietic myeloid progenitors contribute to the ongoing recruitment of pro-inflammatory cells, such as eosinophils and basophils (Eo/B), to target tissue sites in allergic diseases. It is apparent that the development of allergic inflammation is critically dependent on the ability of the bone marrow to support the proliferation, differentiation and mobilization of haemopoietic progenitors. The haemopoietic inductive microenvironment in the bone marrow is crucial for providing signals necessary for maintenance of progenitor populations at varying stages of lineage commitment and permitting these cells to circulate in the bloodstream. Progenitors demonstrate responsiveness to specific cytokines, which varies with stage of differentiation. Pro-inflammatory signals, Th2 cytokines in particular, generated following allergen challenge, can impact on haemopoietic progenitor differentiation and mobilization, leading to accelerated Eo/B production. Allergen inhalation by allergic asthmatics induces a time-dependent change in cytokine levels within the bone marrow compartment, influencing differentiation of Eo/B progenitors, as evidenced by the relationship between increased bone marrow IL-5 levels and Eo/B production. It is proposed that inhaled allergen induces trafficking of IL-5-producing T lymphocytes to the bone marrow, further promoting eosinophilopoiesis through IL-5R signalling. In this manner, Th2 lymphocyte trafficking from the airway may regulate events occurring in the bone marrow. Negative regulators of Eo/B differentiation, including Th1 cytokines, may prove to be important for restoring homeostasis. Eo/B progenitors are also altered in cord blood of infants at risk of atopy and asthma, offering a potential biomarker for, and raising the possibility that Eo/B progenitors are directly involved in the development of allergic disease. For example, changes in the expression of haemopoietic cytokine receptors on cord blood progenitor cells are associated with maternal allergic sensitization, atopic risk and its development, suggesting that haemopoietic processes underlying the allergic phenotype may begin to evolve in the perinatal period.
Subject(s)
Basophils/immunology , Cell Differentiation/immunology , Eosinophils/immunology , Hematopoiesis/immunology , Homeostasis/immunology , Hypersensitivity/immunology , Animals , Biomarkers , Humans , Inflammation/immunology , Inflammation Mediators/immunology , Interleukin-5/immunology , Receptors, Interleukin-5/immunology , Signal Transduction/immunology , Th2 Cells/immunologyABSTRACT
Asthma is a chronic inflammatory disease of the airways characterized by physiological abnormalities of variable airflow obstruction and airway hyperresponsiveness (AHR) to a wide variety of physical and inhaled chemical stimuli and the presence of symptoms. AHR is measured by challenging the airways with a variety of agonists and naturally occurring stimuli, which results in constriction of the airway smooth muscle, leading to airway narrowing and airflow limitation. There are two distinct mechanisms by which the airways can narrow to a constrictor stimulus and these are defined by the pathways they take to induce AHR. Direct stimuli are pharmacological agents administered exogenously (such as histamine or methacholine) that act 'directly' on specific receptors on the bronchial smooth muscle to cause constriction. The other mechanism by which the airway can narrow is via the inhalation of indirect stimuli, which include natural stimuli, such as allergen or exercise, and pharmacological agents such as adenosine monophosphate and hyper-osmotic agents (e.g. hypertonic saline or dry powder mannitol). These stimuli induce airway narrowing 'indirectly' by causing the endogenous release of mediators of bronchoconstriction from airway inflammatory cells. Provoked models of asthma have been extremely valuable in understanding the pathobiology of asthma, in aiding diagnosis, in helping to clarify the mechanisms of actions of effective drugs and in the development of new entities to treat asthma. Some provoked models are valuable clinically, particularly those that measure direct AHR, while others, particularly allergen challenge, have been used in animal models and in humans to study the mechanisms of allergen-induced airway inflammation and the associated physiological changes, as well in the development of new drugs for asthma. An emerging role for measurements of AHR is in the evaluation of the optimal treatment for patients with asthma.
Subject(s)
Asthma/physiopathology , Bronchial Provocation Tests , Models, Biological , Animals , Asthma/diagnosis , Asthma/drug therapy , Asthma, Exercise-Induced/physiopathology , Bronchial Hyperreactivity/physiopathology , Bronchial Provocation Tests/adverse effects , Bronchial Provocation Tests/methods , Bronchoconstriction/physiology , Humans , Respiratory Tract Infections/physiopathology , Virus Diseases/physiopathologyABSTRACT
Montelukast and desloratadine synergistically inhibit the allergen-induced early asthmatic response. Montelukast also suppresses the allergen-induced late asthmatic response, but there are no reports on the effect of desloratadine or the combination on the allergen-induced late asthmatic response. Atopic asthmatics (n = 10) completed a multicentric randomised double-blind crossover study comparing single-dose placebo, 5 mg desloratadine, 10 mg montelukast and the combination administered 2 h prior to allergen inhalation challenge. Methacholine challenges were performed 24 h before and after allergen challenge. Exhaled nitric oxide measurements and sputum inflammatory cell counts were also carried out. All active treatments significantly decreased the late asthmatic response area under the curve. Combination therapy provided the greatest inhibition compared to desloratadine and montelukast. Montelukast was nonsignificantly better than desloratadine but not as effective as the combination. There was a trend towards a decrease in airway responsiveness following montelukast and combination. Montelukast, but not desloratadine or the combination, decreased exhaled NO levels 24 h after allergen. The allergen-induced increase in sputum eosinophil numbers was significantly suppressed at 7 h with desloratadine and combination therapy, and at 24 h with montelukast and combination therapy. Single-dose co-administration of desloratadine and montelukast 2 h prior to allergen inhalation clinically abolished the late asthmatic response and eosinophil recruitment.
Subject(s)
Acetates/therapeutic use , Anti-Asthmatic Agents/therapeutic use , Asthma/drug therapy , Histamine H1 Antagonists, Non-Sedating/therapeutic use , Leukotriene Antagonists/therapeutic use , Loratadine/analogs & derivatives , Quinolines/therapeutic use , Acetates/administration & dosage , Acetates/immunology , Adult , Allergens/immunology , Analysis of Variance , Anti-Asthmatic Agents/administration & dosage , Anti-Asthmatic Agents/immunology , Asthma/immunology , Bronchial Provocation Tests , Cross-Over Studies , Cyclopropanes , Double-Blind Method , Drug Therapy, Combination , Eosinophils , Female , Humans , Leukotriene Antagonists/administration & dosage , Leukotriene Antagonists/immunology , Loratadine/administration & dosage , Loratadine/immunology , Loratadine/therapeutic use , Male , Methacholine Chloride , Middle Aged , Nitric Oxide/metabolism , Placebos , Quinolines/administration & dosage , Quinolines/immunology , Respiratory Function Tests , Sputum/cytology , Sulfides , Treatment OutcomeABSTRACT
BACKGROUND: IVX-0142 is a heparin-derived hypersulfated disaccharide devoid of anticoagulant activity while possessing anti-allergic and anti-inflammatory activity in preclinical studies. In a proof-of-concept study, the allergen inhalation challenge model was used to investigate the effect of IVX-0142 in mild atopic asthma. METHODS: Nineteen subjects, not on controller medications, were randomized to an evaluator-blind, placebo-controlled, cross-over study. The effect of a single nebulized dose of IVX-0142 (80 mg) or placebo administered 30 min prior to allergen inhalation was evaluated on the allergic airway responses, airway responsiveness, and airway inflammation. RESULTS: When compared with placebo, 14 and 13 subjects experienced a relatively smaller maximum fall in forced expiratory volume in 1 s (maxFEV(1)%) for the early airway response (EAR) and late airway response (LAR) with IVX-0142, respectively (P < 0.01). The degree of attenuation in the EAR [maxFEV(1)% (mean +/- SE) 26.5 +/- 2.8%vs placebo 31.0 +/- 2.8%, P = 0.059] and LAR (15.6 +/- 2.9%vs placebo 19.0 +/- 2.9%, P = 0.24) with IVX-0142, however, was small and did not reach statistical significance compared with placebo. Similarly, a trend in the attenuation of allergen-induced increase in the absolute sputum cell counts was also observed. No difference in the allergen-induced increase in airway hyper-responsiveness and exhaled nitric oxide was noticed. CONCLUSIONS: The majority of mild atopic asthmatics demonstrated a reduction in the EAR and LAR to IVX-0142. However, the treatment effect observed with a single prechallenge dose of IVX-0142 was small and heterogeneous. The potential anti-allergic and anti-inflammatory effects using multiple higher doses need to be evaluated.
Subject(s)
Anti-Allergic Agents/pharmacology , Anti-Allergic Agents/therapeutic use , Asthma/drug therapy , Disaccharides/pharmacology , Adult , Asthma/immunology , Cross-Over Studies , Female , Humans , Male , Middle Aged , Severity of Illness Index , Treatment OutcomeABSTRACT
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. METHODS: Peripheral blood was obtained from 16 allergic asthmatic subjects before and at 0.5, 1, 2, 3, 4, 6, 24, and 48 h after inhaled diluent and allergen challenges. Dendritic cells were enumerated using flow cytometry. RESULTS: Allergen inhalation significantly reduced mDCs at 6 h (21.3 +/- 2.0 vs 15.0 +/- 1.8/microl blood; P < 0.05) and 24 h (21.5 +/- 3.4 vs 16.4 +/- 2.4/microl blood; P < 0.05) after challenge. Circulating pDCs were significantly lower than baseline up to 24 h after both allergen and diluent challenges. There was a significant efflux of CCR6(+) mDCs from peripheral blood at 6 h and CCR6(+) pDCs at 4 h after allergen challenge, when compared with diluent. There was no difference in the number of circulating CCR7(+) mDCs or pDCs after diluent or allergen challenges. CONCLUSIONS: Peripheral blood mDCs and CCR6(+) mDCs, but not pDCs, are reduced up to 24 h after allergen inhalation. Thus, allergen inhalation causes trafficking of immature CCR6(+) DCs from blood into the airway, while that of the trafficking of the mature CCR7(+) DCs from the airways into the regional lymph nodes probably occurs through the lymphatic system.
Subject(s)
Asthma/blood , Asthma/immunology , Dendritic Cells/immunology , Myeloid Cells/immunology , Adolescent , Adult , Allergens , Animals , Asthma/chemically induced , Bronchial Provocation Tests/adverse effects , Flow Cytometry , Humans , Leukocytes/drug effects , Leukocytes/metabolism , Lymphocyte Count , Middle Aged , Protein Transport , Receptors, CCR6/blood , Receptors, CCR7/bloodABSTRACT
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-gamma (IFN-gamma) positive CD4+ and CD8+ lymphocytes in peripheral blood and induced sputum. OBJECTIVE: This study examined the effects of an inhaled corticosteroid on these previously described allergen-induced changes in circulating Th1 and Th2 lymphocytes. METHODS: Subjects were randomized to 7 days of placebo, 40 or 80 micro g ciclesonide in a crossover study. Airway responses and peripheral blood were measured before and after treatment, and 24 h after allergen challenge. RESULTS: Ciclesonide 40 and 80 micro g significantly attenuated the late response and sputum eosinophils at 8 h post-allergen (P<0.05). Circulating IFN-gamma positive CD4+ lymphocytes decreased after allergen challenge with placebo (P<0.05), and this was inhibited by 40 micro g ciclesonide treatment (P<0.05). There was no effect of allergen inhalation or ciclesonide on IL-4-positive CD4+ lymphocytes or IFN-gamma and IL-4-positive CD8(high) lymphocytes. The allergen-induced change of IFN-gamma/IL-4 ratio on CD4+ cells correlated with the allergen-induced change of peripheral blood eosinophils. CONCLUSIONS: The results of this study suggest that attenuation of allergen-induced airway responses by ciclesonide may be mediated through regulation of IFN-gamma-positive CD4+ cells.
Subject(s)
Asthma/drug therapy , CD4-Positive T-Lymphocytes/immunology , Glucocorticoids/administration & dosage , Hypersensitivity/drug therapy , Pregnenediones/administration & dosage , Administration, Inhalation , Adult , Allergens , Analysis of Variance , Asthma/immunology , Biomarkers/analysis , Bronchial Provocation Tests , CD8-Positive T-Lymphocytes/immunology , Cross-Over Studies , Double-Blind Method , Drug Administration Schedule , Eosinophils/immunology , Female , Flow Cytometry , Glucocorticoids/therapeutic use , Humans , Hypersensitivity/immunology , Interferon-gamma/analysis , Interleukin-4/analysis , Lymphocyte Count , Male , Methacholine Chloride , Pregnenediones/therapeutic use , Sputum/immunologyABSTRACT
BACKGROUND: The allergen-induced early asthmatic response [provocation concentration (PC)20, the concentration causing a 20% forced expiratory volume in 1 s (FEV)1 fall] depends on the level of IgE sensitivity and the degree of nonallergic airway hyperresponsiveness (AHR) and can be predicted from histamine PC20 and allergen skin test endpoint. OBJECTIVES: We examined the relationships between allergen PC20, methacholine PC20, and allergen skin test endpoint and assessed the accuracy of both the histamine PC20-based prediction of allergen PC20 (using methacholine) and a new methacholine PC20-based prediction equation. METHODS: From 158 allergen challenges, the allergen PC20, the methacholine PC20, and the skin test endpoint were recorded and relationships between these three were sought. We compared the measured allergen PC20 to that predicted from the previous histamine PC20-based and the new methacholine-based formulae. RESULTS: In single regressions, allergen PC20 correlated with both methacholine PC20 (r=0.25, P=0.0015) and skin test endpoint (r=0.52, P <0.00005). The relationship was improved by multiple regression of log-allergen PC20vs. log-methacholine PC20 and log-endpoint (r=0.61, P <0.00005). The histamine-based formula predicted allergen PC20 to within 2 doubling concentrations in 80% and within 3 in 92%. The new methacholine-based formula to within 2 and 3 concentrations in 81% and 94%, respectively; only nine of 158 subjects were outside the 3 concentrations. CONCLUSIONS: We have confirmed the dependence of the allergen-induced early asthmatic response upon the level of allergic sensitivity and the degree of AHR, the latter as assessed by methacholine challenge. The allergen PC20 can be predicted to within 3 doubling concentrations in 94% of cases.