RESUMO
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.
Assuntos
Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Compostos Orgânicos/uso terapêutico , Receptores CCR3/antagonistas & inibidores , Adulto , Alérgenos/efeitos adversos , Alérgenos/imunologia , Testes de Provocação Brônquica , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , MasculinoRESUMO
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.
Assuntos
Alérgenos/imunologia , Hipersensibilidade/diagnóstico , Hipersensibilidade/imunologia , Escarro/citologia , Escarro/imunologia , Alérgenos/administração & dosagem , Animais , Asma/diagnóstico , Asma/imunologia , Testes de Provocação Brônquica , Granulócitos/imunologia , Granulócitos/metabolismo , Humanos , Imunização , Imunoglobulina E/imunologia , Camundongos , Estudos Retrospectivos , Testes CutâneosRESUMO
BACKGROUND: Haemopoietic progenitor cells (HPC) migrate to sites of allergic inflammation where, upon stimulation with epithelial cytokines, they produce Th2 cytokines and differentiate into mature eosinophils and basophils. They also express Toll-like receptors (TLR) involved in antimicrobial responses. OBJECTIVE: The objective of this study was to compare TLR expression on peripheral blood HPC and TLR-induced responses, in particular changes in epithelial cytokine receptors, in healthy and asthmatic subjects at baseline and following allergen challenge. METHODS: Ten healthy and 11 allergic asthmatic subjects were studied. HPC-enriched cell populations were stimulated with TLR-2, TLR-4 or TLR-9 ligands. TLR expression by circulating HPC and interleukin (IL)-25 (IL-17RB), IL-33 (ST2) and thymic stromal lymphopoietin receptor (TSLPR) expression after TLR ligation were examined by flow cytometry at baseline and, in asthmatics, following allergen challenge. The effects of dexamethasone (Dex) on TLR-induced responses were also assessed. RESULTS: Asthmatics had significantly lower circulating HPC expressing TLR-2 and TLR-9 with a similar trend for TLR-4. TLR-4 stimulation of HPC yielded higher numbers of TSLPR+ cells in asthmatics compared with healthy subjects. A similar trend was seen for TLR-9 ligation, an effect further augmented by allergen inhalation. Allergen challenge also enhanced TLR-induced ST2 expression on HPC. Treatment with Dex in vitro increased TLR-4-induced TSLPR expression but had no effect on other epithelial cytokine receptors. CONCLUSIONS AND CLINICAL RELEVANCE: These data demonstrate an interaction between allergen and TLR ligand exposure in asthmatics. Allergen inhalation augments the TLR-induced inflammatory response by HPC, possibly leading to increased "in situ haemopoiesis" through up-regulation of TSLPR. These findings show that HPC may be a part of the pro-inflammatory cascade in pathogen-induced asthma exacerbation through their increased responsiveness to TLR stimulation.
Assuntos
Asma/etiologia , Asma/metabolismo , Regulação da Expressão Gênica , Células-Tronco Hematopoéticas/metabolismo , Receptores de Citocinas/genética , Mucosa Respiratória/metabolismo , Receptores Toll-Like/metabolismo , Adolescente , Adulto , Idoso , Alérgenos/imunologia , Asma/diagnóstico , Asma/terapia , Basófilos/imunologia , Basófilos/metabolismo , Estudos Cross-Over , Citocinas/metabolismo , Humanos , Macrófagos/imunologia , Macrófagos/metabolismo , Pessoa de Meia-Idade , Neutrófilos/imunologia , Neutrófilos/metabolismo , Testes de Função Respiratória , Mucosa Respiratória/imunologia , Mucosa Respiratória/patologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Adulto JovemRESUMO
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.
Assuntos
Eosinófilos/imunologia , Eosinófilos/metabolismo , Expressão Gênica , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Imunomodulação/genética , Adulto , Alérgenos/administração & dosagem , Alérgenos/imunologia , Asma/diagnóstico , Asma/genética , Asma/imunologia , Asma/metabolismo , Testes de Provocação Brônquica , Feminino , Humanos , Masculino , Cloreto de Metacolina/administração & dosagem , Pessoa de Meia-Idade , Testes de Função Respiratória , Adulto JovemRESUMO
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.
Assuntos
Alérgenos/imunologia , Asma/tratamento farmacológico , Asma/imunologia , Antagonistas de Leucotrienos/uso terapêutico , Receptores de Leucotrienos/metabolismo , Adulto , Asma/diagnóstico , Asma/metabolismo , Butiratos/farmacologia , Butiratos/uso terapêutico , Expiração , Feminino , Humanos , Indóis/farmacologia , Indóis/uso terapêutico , Antagonistas de Leucotrienos/farmacologia , Masculino , Óxido Nítrico/metabolismo , Testes de Função Respiratória , Escarro/citologia , Resultado do Tratamento , Adulto JovemRESUMO
Asthma is characterized by discordant responses among cells of the adaptive and innate immune systems. This interplay involves a complex pattern of cytokine-driven processes resulting in cell migration and recruitment, inflammation, and proliferative states. The significant majority of asthmatic patients respond well to conventional inhaled treatments. However, about 5% of asthmatics have severe refractory asthma and account for 50% of the health expenditure on asthma. Human(ized) monoclonal antibodies (hMabs) targeting inflammatory pathways are promising therapeutic agents in asthma management. The anti-IgE hMab omalizumab was the first biologic treatment approved for the treatment of allergic asthma. Potential future strategies and targets include interleukin (IL)-5, IL-4, and IL-13, anti-TSLP, IL-25, and IL-33. hMabs targeting IL-5 have shown great promise in severe refractory asthma with a persisting eosinophilia, and clinical trials with hMabs against IL-13 and IL4Rα have also shown clinical benefit. Studies of hMabs against other cytokines in severe asthma are under way.
Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Asma/tratamento farmacológico , Mediadores da Inflamação/antagonistas & inibidores , Terapia de Alvo Molecular/métodos , Humanos , Modelos ImunológicosRESUMO
BACKGROUND: Roflumilast, a phosphodiesterase-4 inhibitor, has an established place in the treatment of chronic obstructive pulmonary disease. Its potential role as a treatment for asthma is unclear. AIM: We report the results from seven double-blind, parallel group, phase II or III studies designed to compare roflumilast with two anti-inflammatory treatments, beclomethasone dipropionate (BDP) and montelukast, in patients with asthma. METHODS: The studies of 6-12 week duration were conducted at 309 sites in Europe, North America, South Africa and Australia from 1998 to 2005. Data from 3802 patients, aged 12-70 years who received either roflumilast 100 µg, 250 µg or 500 µg once daily, BDP 400 µg or 500 µg twice daily, or 10 mg montelukast once daily was analyzed. Primary endpoints were mean change and time averaged excess area under the curve in forced expiratory volume in one second (FEV1) over the duration of the study. Secondary endpoints included change in forced vital capacity and peak expiratory flow, asthma symptoms and the concomitant use of rescue medication. RESULTS: Roflumilast was non-inferior to BDP and montelukast and consistently increased FEV1. Use of rescue medication and all asthma symptom scores decreased significantly with all treatments, but no statistically significant between-group differences were observed. Secondary lung function endpoints generally supported the conclusions of the primary outcome measure. CONCLUSIONS: Roflumilast improves FEV1 and asthma symptoms in patients with mild to moderate asthma, and is non-inferior compared with both BDP and montelukast. It deserves further study as a potentially effective anti-inflammatory treatment for asthma.
Assuntos
Acetatos/uso terapêutico , Aminopiridinas/uso terapêutico , Asma/tratamento farmacológico , Beclometasona/uso terapêutico , Benzamidas/uso terapêutico , Inibidores da Fosfodiesterase 4/uso terapêutico , Quinolinas/uso terapêutico , Adolescente , Adulto , Idoso , Aminopiridinas/administração & dosagem , Asma/fisiopatologia , Benzamidas/administração & dosagem , Criança , Ciclopropanos/administração & dosagem , Ciclopropanos/uso terapêutico , Método Duplo-Cego , Volume Expiratório Forçado , Humanos , Pessoa de Meia-Idade , Sulfetos , Adulto JovemAssuntos
Aminopiridinas/uso terapêutico , Asma/tratamento farmacológico , Benzamidas/uso terapêutico , Inibidores da Fosfodiesterase 4/uso terapêutico , Administração por Inalação , Corticosteroides/administração & dosagem , Aminopiridinas/efeitos adversos , Benzamidas/efeitos adversos , Ciclopropanos/efeitos adversos , Ciclopropanos/uso terapêutico , HumanosRESUMO
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.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Asma/tratamento farmacológico , Asma/imunologia , Contagem de Linfócito CD4 , Citocinas/antagonistas & inibidores , Ligante OX40/antagonistas & inibidores , Linfócitos T Reguladores/imunologia , Adulto , Anticorpos Monoclonais/farmacologia , Asma/fisiopatologia , Feminino , Volume Expiratório Forçado , Humanos , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Linfócitos T Reguladores/metabolismo , Resultado do Tratamento , Adulto Jovem , Linfopoietina do Estroma do TimoRESUMO
BACKGROUND: An unresolved issue in T regulatory cells' cell biology is the lack of consensus on phenotypic markers that accurately define the natural Treg (nTreg) population. OBJECTIVES: To examine nTreg frequency and functional capacity in healthy controls and their frequency in asthmatic subjects using three different phenotypic strategies. We hypothesized that phenotypically different nTreg are quantitatively and functionally different. METHODS: Thirty-four healthy, non-asthmatic and 17 asthmatic subjects were studied. Three nTreg phenotypes were defined as follows: nTreg1 (CD4(+) CD25(+) Foxp3(+) ), nTreg2 (CD4(+) CD25(+) CD127(low) Foxp3(+) ), and nTreg3 (CD4(+) CD25(high) Foxp3(+) ). The flow cytometric determination of nTreg frequency in peripheral blood (PB) and bronchoalveolar lavage (BAL) was performed using fluorescently labelled antibodies. Peripheral blood nTreg functional capacity was assessed using a CFSE-based suppression assay. RESULTS: There was a significantly lower frequency of PB nTreg3 compared to nTreg2 and nTreg1 (P < 0.05). Both nTreg2 and nTreg3 had a significantly greater suppressive capacity than nTreg1 at T responder (Tresp) to nTreg ratios of 16 : 1 up to 1 : 1 (P < 0.01). Asthmatics exhibited a significantly lower PB nTreg3 and nTreg1 frequency than healthy controls (P < 0.05). There were no differences between healthy controls and asthmatic subjects when comparing BAL nTreg frequency. CONCLUSIONS AND CLINICAL RELEVANCE: Phenotypically different nTreg subsets are quantitatively and functionally different and are variably observed in asthma. The CD4(+) CD25(high) Foxp3(+) phenotype was the least frequent, but demonstrated the greatest suppression, and was significantly lower in PB of asthmatic subjects. Consequently, it is imperative that nTreg phenotypes be clearly defined and that the interpretation of their frequency and function be phenotype specific.
Assuntos
Asma/imunologia , Asma/metabolismo , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Fenótipo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Adulto , Antígenos de Superfície/metabolismo , Asma/fisiopatologia , Contagem de Linfócito CD4 , Estudos de Casos e Controles , Feminino , Fatores de Transcrição Forkhead/metabolismo , Humanos , Imunofenotipagem , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: The allergen bronchoprovocation (ABP) test is a validated model to study asthma pathophysiology and response to treatments. The inhibitory effect of agents on the allergen-induced late asthmatic response (LAR) is a predictor of their efficacy in asthma treatment. However, it is difficult to predict the magnitude of a LAR, which may vary according to immune responsiveness and the type of allergen used for ABP. AIM: To determine the relationship between the magnitudes of early asthmatic response (EAR) and LAR in mild asthmatic subjects according to the type of allergen inhaled and its determinants. METHODS: This is a retrospective analysis of a large database of ABPs, all performed with a common standardized methodology. Patients were either challenged with house dust mites (HDMs), animals or pollens allergens. EAR was defined as a ≥ 20% fall in forced expiratory volume in 1 s (FEV1 ) < 3 h following ABP and LAR as a ≥ 15% fall in FEV1 between 3 and 7 h post-ABP. The ratio of EAR % fall in FEV1 /LAR % fall in FEV1 was compared between the groups of subjects according to the allergen used for ABP. RESULTS: Data from 290 subjects were analysed: 87 had an isolated EAR and 203 had a dual response (EAR + LAR). Dual responders had a significantly lower baseline PC20 , a more marked fall in FEV1 at EAR, and a trend towards higher baseline sputum eosinophil percentages. The ratio of EAR over LAR was significantly lower in HDM compared with pollen ABP, indicating a larger LAR for a similar EAR. No correlations were observed between the ratio of EAR over LAR and the various parameters recorded in the different groups analysed. CONCLUSION: Different mechanisms may be involved in modulating the magnitude of the LAR, according to the type of allergen. HDM seems to induce a stronger LAR than pollens, animal allergens being intermediary in this regard.
Assuntos
Alérgenos/imunologia , Asma/imunologia , Estações do Ano , Adulto , Asma/diagnóstico , Asma/fisiopatologia , Testes de Provocação Brônquica , Eosinófilos/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes de Função Respiratória , Estudos Retrospectivos , Escarro/imunologia , Adulto JovemRESUMO
BACKGROUND: Inhaled glucocorticosteroids (ICS) are the mainstay of treatment in asthma. Fluticasone furoate (FF) is a novel, once-daily ICS asthma therapy. This study investigated the efficacy and safety of FF 50 mcg in patients with mild-to-moderate persistent asthma. METHODS: A 24-week, multicenter, randomized, placebo-controlled and active-controlled, double-blind, double-dummy, parallel-group phase III study. Three hundred and fifty-one patients (aged ≥12 years; uncontrolled by non-ICS therapy) were randomized to treatment (1 : 1 : 1) with once-daily FF 50 mcg dosed in the evening, twice-daily fluticasone propionate (FP) 100 mcg or placebo. The primary endpoint was change from baseline in evening trough forced expiratory volume in 1 s (FEV1 ) at Week 24. Secondary endpoints were change from baseline in the percentage of rescue-free 24-h periods (powered endpoint), change from baseline in evening and morning peak expiratory flow, change from baseline in the percentage of symptom-free 24-h periods and number of withdrawals due to lack of efficacy. RESULTS: Evening trough FEV1 at Week 24 was not statistically significantly increased with FF 50 mcg once-daily (37 ml [95% CI: -55, 128]; P = 0.430), but was with FP 100 mcg twice daily (102 ml [10, 194]; P = 0.030), vs placebo. No consistent trends were observed across other endpoints, including the powered secondary endpoint. No safety concerns were raised for either active treatment. CONCLUSIONS: FP 100 mcg twice daily improved evening trough FEV1 in patients with mild-to-moderate persistent asthma, but FF 50 mcg once daily did not demonstrate a significant effect. Secondary endpoints showed variable results. No safety concerns were identified for FF or FP.
Assuntos
Androstadienos/administração & dosagem , Antiasmáticos/administração & dosagem , Asma/tratamento farmacológico , Adolescente , Adulto , Androstadienos/efeitos adversos , Antiasmáticos/efeitos adversos , Asma/diagnóstico , Esquema de Medicação , Feminino , Volume Expiratório Forçado , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: 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. OBJECTIVE: To investigate changes in circulating and sputum mDC2s after allergen inhalation in subjects with asthma. METHODS: Peripheral blood and induced sputum were obtained before and 3, 7, and 24 h 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. RESULTS: The number of sputum mDC2s significantly increased 24 h after allergen challenge compared with diluent. The expression of BDCA-3 on sputum mDCs also increased, albeit non-significantly, at 7 and 24 h after allergen. Soluble BDCA-3 in sputum and the number of circulating mDC2s were not different between allergen and diluent. CONCLUSIONS AND CLINICAL RELEVANCE: Myeloid DCs type 2 (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.
Assuntos
Alérgenos/imunologia , Asma/imunologia , Células Dendríticas/imunologia , Células Mieloides/imunologia , Administração por Inalação , Adolescente , Adulto , Idoso , Alérgenos/administração & dosagem , Antígenos de Superfície/metabolismo , Asma/metabolismo , Asma/fisiopatologia , Células Dendríticas/metabolismo , Feminino , Humanos , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Células Mieloides/metabolismo , Escarro/citologia , Escarro/imunologia , Trombomodulina , Adulto JovemRESUMO
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.
Assuntos
Alérgenos/imunologia , Antiasmáticos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Asma/tratamento farmacológico , Asma/imunologia , Ligante de CD40/antagonistas & inibidores , Adulto , Antiasmáticos/efeitos adversos , Antiasmáticos/farmacologia , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacologia , Asma/metabolismo , Antígenos CD40/metabolismo , Ligante de CD40/metabolismo , Células Dendríticas/imunologia , Eosinófilos , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Transdução de Sinais/efeitos dos fármacos , Linfócitos T/imunologia , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: A recent case-controlled study reported an increased risk of diabetes mellitus in patients treated with inhaled corticosteroids for asthma or COPD, versus age-matched controls. OBJECTIVE: The purpose of the current study was to evaluate whether there was an increased risk of new onset diabetes mellitus or hyperglycaemia among patients with asthma or COPD treated with inhaled corticosteroids. METHODS: A retrospective analysis evaluated all double-blind, placebo-controlled, trials in patients ≥4 years of age involving budesonide or budesonide/formoterol in asthma (26 trials; budesonide: n = 9067; placebo: n = 5926), and in COPD (8 trials; budesonide: n = 4616; non-ICS: n = 3643). A secondary dataset evaluated all double-blind, controlled trials in asthma involving the use of inhaled corticosteroids (60 trials; budesonide: n = 33,496; fluticasone: n = 2773). RESULTS: In the primary asthma dataset, the occurrence of diabetes mellitus/hyperglycaemia adverse events (AEs) was 0.13% for budesonide and 0.13% for placebo (HR 0.98 [95% CI: 0.38-2.50], p = 0.96) and serious adverse events (SAEs) was 0% for budesonide and 0.05% for placebo. In the secondary dataset, the occurrence of diabetes/hyperglycaemia as AE and SAE was 0.19% and 0.03%, respectively. In the COPD dataset, the occurrence of diabetes mellitus/hyperglycaemia AEs was 1.3% for budesonide and 1.2% for non-ICS (HR 0.99 [95% CI: 0.67-1.46], p = 0.96) and SAEs was 0.1% for budesonide and 0.03% for non-ICS. CONCLUSION AND CLINICAL RELEVANCE: Treatment with inhaled corticosteroids in patients with asthma or COPD was not associated with increased risk of new onset diabetes mellitus or hyperglycaemia.
Assuntos
Corticosteroides/efeitos adversos , Antiasmáticos/efeitos adversos , Asma/tratamento farmacológico , Diabetes Mellitus/induzido quimicamente , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Administração por Inalação , Corticosteroides/administração & dosagem , Adulto , Androstadienos/administração & dosagem , Androstadienos/efeitos adversos , Antiasmáticos/administração & dosagem , Budesonida/administração & dosagem , Budesonida/efeitos adversos , Método Duplo-Cego , Etanolaminas/administração & dosagem , Etanolaminas/efeitos adversos , Fluticasona , Fumarato de Formoterol , Humanos , Hiperglicemia/induzido quimicamente , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Fatores de RiscoRESUMO
BACKGROUND: Increased numbers of neutrophils are reported in the airways of patients with severe asthma. It is not clear if they contribute to the lack of control and severity. There are currently no strategies to investigate this by decreasing neutrophil numbers in the airways. OBJECTIVE: To investigate the safety and efficacy of SCH527123, a selective CXCR2 receptor antagonist, in patients with severe asthma and increased number of neutrophils in sputum. METHODS: In a randomized, double-blind, parallel study, patients with severe asthma and sputum total cell count < 10 × 10(6) /g and neutrophils > 40% were randomized to SCH527123, 30 mg daily PO (n = 22) or placebo (n = 12) for 4 weeks. Primary end-points were safety and change in sputum and blood neutrophil counts. Secondary end-points were change in asthma control questionnaire (ACQ) score, minor and major exacerbations, spirometry and sputum neutrophil activation markers. RESULTS: The SCH 527123 caused a mean reduction of 36.3% in sputum neutrophil percentage compared to a 6.7% increase in the placebo arm (P = 0.03). The mean absolute neutrophil count in blood was reduced by 14% at the end of 4 weeks, but recovered by the 5th week. There were no differences in the overall rates of adverse events among the groups. There were fewer mild exacerbations (1.3 vs. 2.25, P = 0.05) and a trend towards improvement in the ACQ score (mean difference between groups of 0.42 points, P = 0.053). No statistically significant changes were observed in forced expiratory volume in 1 s (FEV (1)), sputum myeloperoxidase, IL8 or elastase. CONCLUSIONS: The SCH527123 is safe and reduces sputum neutrophils in patients with severe asthma. CLINICAL RELEVANCE: This new treatment provides an opportunity to investigate the role of neutrophils in severe asthma with potential clinical benefits. Larger studies of longer duration are needed to evaluate the impact on other outcomes of asthma including exacerbations.
Assuntos
Asma/tratamento farmacológico , Asma/metabolismo , Benzamidas/administração & dosagem , Ciclobutanos/administração & dosagem , Neutrófilos/metabolismo , Receptores de Interleucina-8B/antagonistas & inibidores , Escarro , Adolescente , Adulto , Idoso , Asma/patologia , Benzamidas/efeitos adversos , Biomarcadores/metabolismo , Contagem de Células , Ciclobutanos/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Interleucina-8/metabolismo , Masculino , Pessoa de Meia-Idade , Ativação de Neutrófilo/efeitos dos fármacos , Neutrófilos/patologia , Elastase Pancreática/metabolismo , Peroxidase/metabolismo , Índice de Gravidade de DoençaRESUMO
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.
Assuntos
Asma/terapia , Antiasmáticos/uso terapêutico , Broncodilatadores/uso terapêutico , Humanos , Hipertermia Induzida , Inflamação/terapia , Índice de Gravidade de DoençaRESUMO
BACKGROUND AND PURPOSE: Inhaled corticosteroids (ICS) are the cornerstone of asthma pharmacotherapy and, acting via the glucocorticoid receptor (GR), reduce inflammatory gene expression. While this is often attributed to a direct inhibitory effect of the GR on inflammatory gene transcription, corticosteroids also induce the expression of anti-inflammatory genes in vitro. As there are no data to support this effect in asthmatic subjects taking ICS, we have assessed whether ICS induce anti-inflammatory gene expression in subjects with atopic asthma. EXPERIMENTAL APPROACH: Bronchial biopsies from allergen-challenged atopic asthmatic subjects taking inhaled budesonide or placebo were subjected to gene expression analysis using real-time reverse transcriptase-PCR for the corticosteroid-inducible genes (official gene symbols with aliases in parentheses): TSC22D3 [glucocorticoid-induced leucine zipper (GILZ)], dual-specificity phosphatase-1 (MAPK phosphatase-1), both anti-inflammatory effectors, and FKBP5 [FK506-binding protein 51 (FKBP51)], a regulator of GR function. Cultured pulmonary epithelial and smooth muscle cells were also treated with corticosteroids before gene expression analysis. KEY RESULTS: Compared with placebo, GILZ and FKBP51 mRNA expression was significantly elevated in budesonide-treated subjects. Budesonide also increased GILZ expression in human epithelial and smooth muscle cells in culture. Immunostaining of bronchial biopsies revealed GILZ expression in the airways epithelium and smooth muscle of asthmatic subjects. CONCLUSIONS AND IMPLICATIONS: Expression of the corticosteroid-induced genes, GILZ and FKBP51, is up-regulated in the airways of allergen-challenged asthmatic subjects taking inhaled budesonide. Consequently, the biological effects of corticosteroid-induced genes should be considered when assessing the actions of ICS. Treatment modalities that increase or decrease GR-dependent transcription may correspondingly affect corticosteroid efficacy.
Assuntos
Corticosteroides/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Asma/genética , Broncodilatadores/uso terapêutico , Budesonida/uso terapêutico , Expressão Gênica/efeitos dos fármacos , Administração por Inalação , Alérgenos/farmacologia , Asma/tratamento farmacológico , Linhagem Celular Tumoral , Estudos Cross-Over , Fosfatase 1 de Especificidade Dupla/genética , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Humanos , Pulmão/citologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteínas de Ligação a Tacrolimo/genética , Fatores de Transcrição/genéticaAssuntos
Asma/imunologia , Hipersensibilidade/imunologia , Interleucina-18/imunologia , Receptores de Interleucina-18/imunologia , Asma/metabolismo , Feminino , Humanos , Hipersensibilidade/metabolismo , Interleucina-18/metabolismo , Masculino , Pessoa de Meia-Idade , Receptores de Interleucina-18/metabolismo , Adulto JovemRESUMO
The origins of allergic asthma, particularly in infancy, remain obscure. Respiratory viral infections and allergen sensitization in early life have been associated with asthma in young children. However, a causal link has not been established. We investigated whether an influenza A infection in early life alters immune responses to house dust mite (HDM) and promotes an asthmatic phenotype later in life. Neonatal (8-day-old) mice were infected with influenza virus and 7 days later, exposed to HDM for 3 weeks. Unlike adults, neonatal mice exposed to HDM exhibited negligible immune responsiveness to HDM, but not to influenza A. HDM responsiveness in adults was associated with distinct Ly6c+ CD11b+ inflammatory dendritic cell and CD8α+ plasmacytoid (pDC) populations that were absent in HDM-exposed infant mice, suggesting an important role in HDM-mediated inflammation. Remarkably, HDM hyporesponsiveness was overcome when exposure occurred concurrently with an acute influenza infection; young mice now displayed robust allergen-specific immunity, allergic inflammation, and lung remodeling. Remodeling persisted into early adulthood, even after prolonged discontinuation of allergen exposure and was associated with marked impairment of lung function. Our data demonstrate that allergen exposure coincident with acute viral infection in early life subverts constitutive allergen hyporesponsiveness and imprints an asthmatic phenotype in adulthood.