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RATIONALE AND OBJECTIVE: Benralizumab induces rapid and near-complete depletion of eosinophils from blood and lung tissue. We investigated whether benralizumab could attenuate allergen-induced late asthmatic responses (LAR) in participants with allergic asthma. METHODS AND MEASUREMENTS: Participants with allergic asthma who demonstrated increased sputum eosinophils and LAR at screening were randomised to benralizumab 30â mg or matched placebo given every 4 weeks for 8 weeks (3 doses). Allergen challenges were performed at weeks 9 and 12 when blood, sputum, bone marrow and bronchial tissue eosinophils and LAR were assessed. MAIN RESULTS: Forty-six participants (mean age, 30.9 years) were randomised to benralizumab (n = 23) or placebo (n = 23). Eosinophils were significantly reduced in the benralizumab group compared with placebo in blood at 4 weeks and sputum and bone marrow at 9 weeks after treatment initiation. At 7â h after an allergen challenge at week 9, sputum eosinophilia was significantly attenuated in the benralizumab group compared to placebo (least squares mean difference -5.81% [95% CI, -10.69, -0.94]; P = 0.021); however, the LAR was not significantly different (least squares mean difference 2.54% [95% CI, 3.05, 8.12]; P = 0.363). Adverse events were reported for 7 (30.4%) and 14 (60.9%) participants in the benralizumab and placebo groups, respectively. CONCLUSION: Benralizumab administration over 8 weeks resulted in a significant attenuation of blood, bone marrow and sputum eosinophilia in participants with mild allergic asthma; however, there was no change in the LAR, suggesting that eosinophils alone are not a key component of allergen-induced bronchoconstriction.
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BACKGROUND: The immune response dynamics in COVID-19 patients remain a subject of intense investigation due to their implications for disease severity and treatment outcomes. We examined changes in leukocyte levels, eosinophil activity, and cytokine profiles in patients hospitalized with COVID-19. METHODS: Serum samples were collected within the first 10 days of hospitalization/confirmed infection and analyzed for eosinophil granule proteins (EGP) and cytokines. Information from medical records including comorbidities, clinical symptoms, medications, and complete blood counts were collected at the time of admission, during hospitalization and at follow up approximately 3 months later. RESULTS: Serum levels of eotaxin, type 1 and type 2 cytokines, and alarmin cytokines were elevated in COVID-19 patients, highlighting the heightened immune response (p < 0.05). However, COVID-19 patients exhibited lower levels of eosinophils and eosinophil degranulation products compared to hospitalized controls (p < 0.05). Leukocyte counts increased consistently from admission to follow-up, indicative of recovery. CONCLUSION: Attenuated eosinophil activity alongside elevated chemokine and cytokine levels during active infection, highlights the complex interplay of immune mediators in the pathogenesis COVID-19 and underscores the need for further investigation into immune biomarkers and treatment strategies.
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Biomarcadores , COVID-19 , Citocinas , Eosinófilos , SARS-CoV-2 , Humanos , COVID-19/inmunología , COVID-19/sangre , Masculino , Biomarcadores/sangre , Femenino , Persona de Mediana Edad , Eosinófilos/inmunología , Citocinas/sangre , Anciano , SARS-CoV-2/inmunología , Recuento de Leucocitos , Adulto , Hospitalización , Quimiocina CCL11/sangreRESUMEN
RATIONALE: In asthma, sputum group 2 innate lymphoid cells (ILC2) are activated within 7h after allergen challenge. Neuroimmune interactions mediate rapid host responses at mucosal interfaces. In murine models of asthma, lung ILC2 co-localize to sensory neuronal termini expressing the neuropeptide, neuromedin U (NMU) and NMU stimulates type 2 cytokines secretion by ILC2 with additive effects to alarmins, in vitro. OBJECTIVES: Investigate effect of NMU/NMUR1 axis on early activation of ILC2 in asthma. METHODS: M ild asthmatics (n=8) were enrolled in a diluent-controlled, allergen-inhalation challenge study. Sputum ILC2 expression of NMU receptor 1 (NMUR1) and T2 cytokines were enumerated by flow cytometry and airway NMU levels were assessed by ELISA. This was compared to samples from moderate-severe asthmatics (n=9). Flow sort-purified and ex-vivo expanded ILC2 were used for functional assays and transcriptomic analyses. RESULTS: Significant increases in sputum ILC2 expressing NMUR1 were detected 7h post- allergen versus diluent challenge where the majority of NMUR1+ILC2 expressed IL-5/IL-13. Sputum NMUR1+ILC2 were significantly greater in mild versus moderate-severe asthmatics and NMUR1+ILC2 correlated inversely with the dose of inhaled corticosteroid in the latter group. Co-culturing with alarmins upregulated NMUR1 in ILC2, which was attenuated by dexamethasone. NMU stimulated T2 cytokine expression by ILC2, maximal at 6h was abrogated by dexamethasone or specific signaling inhibitors for mitogen-activated protein kinase ½, phospho-inositol 3 kinase but not IL-33 signaling moiety MyD88, in vitro. CONCLUSIONS: The NMU/NMUR1 axis stimulates rapid effects on ILC2, and maybe an important early activator of these cells in eosinophilic inflammatory responses in asthma.
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This issue highlights and details the program and scientific presentations at the International Eosinophil Society's 12th biennial symposium, which was held in Hamilton, Ontario, Canada, in July 2023. The meeting included sessions on regulation of eosinophil development; cell death, stress, and autophagy in eosinophils; local immunity interactions of eosinophils with multiple cell types; eosinophils in host defense; eosinophils and mast cells in gastrointestinal disorders; reciprocal interactions between eosinophils and the microbiome in homeostasis and dysbiosis; and eosinophils in tissue injury and repair and in tumor biology and cancer therapy. There was a mixture of special invited lectures and cutting-edge abstracts on specific aspects of eosinophil science, as well as enlivened pro-con debates on targeting eosinophils with biologics. A major thrust and overarching theme was that eosinophils exhibit remarkable plasticity and heterogeneity in executing their functions both in homeostasis and in pathobiology; there is a new "eo-verse" to understand. We trust that this special volume of the Journal of Leukocyte Biology will be of interest across many disciplines and medical subspecialties in biomedical sciences and demonstrate both the complexity and versatility of the eosinophil in biology and medicine.
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Eosinófilos , Humanos , Eosinófilos/inmunología , Animales , Plasticidad de la Célula/inmunología , Congresos como Asunto , Homeostasis/inmunologíaRESUMEN
Disruption of the airway epithelium triggers a defensive immune response that begins with the production and release of alarmin cytokines. These epithelial-derived alarmin cytokines, including thymic stromal lymphopoietin (TSLP), are produced in response to aeroallergens, viruses, and toxic inhalants. An alarmin response disproportionate to the inhaled trigger can exacerbate airway diseases such as asthma. Allergens inhaled into previously sensitized airways are known to drive a T2 inflammatory response through the polarization of T cells by dendritic cells mediated by TSLP. Harmful compounds found within air pollution, microbes, and viruses are also triggers causing airway epithelial cell release of TSLP in asthmatic airways. The release of TSLP leads to the development of inflammation which, when unchecked, can result in asthma exacerbations. Genetic and inheritable factors can contribute to the variable expression of TSLP and the risk and severity of asthma. This paper will review the various triggers and consequences of TSLP release in asthmatic airways.
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Asma , Citocinas , Linfopoyetina del Estroma Tímico , Asma/metabolismo , Humanos , Citocinas/metabolismo , Animales , Alérgenos/inmunología , Alarminas/metabolismoRESUMEN
BACKGROUND: Similar immune responses in the nasal and bronchial mucosa implies that nasal allergen challenge (NAC) is a suitable early phase experimental model for drug development targeting allergic rhinitis (AR) and asthma. We assessed NAC reproducibility and the effects of intranasal corticosteroids (INCS) on symptoms, physiology, and inflammatory mediators. METHODS: 20 participants with mild atopic asthma and AR underwent three single blinded nasal challenges each separated by three weeks (NCT03431961). Cohort A (n = 10) underwent a control saline challenge, followed by two allergen challenges. Cohort B (n = 10) underwent a NAC with no treatment intervention, followed by NAC with 14 days pre-treatment with saline nasal spray (placebo), then NAC with 14 days pre-treatment with INCS (220 µg triamcinolone acetonide twice daily). Nasosorption, nasal lavage, blood samples, forced expiratory volume 1 (FEV1), total nasal symptom score (TNSS), peak nasal inspiratory flow (PNIF) were collected up to 24 h after NAC. Total and active tryptase were measured as early-phase allergy biomarkers (≤30 min) and IL-13 and eosinophil cell counts as late-phase allergy biomarkers (3-7 h) in serum and nasal samples. Period-period reproducibility was assessed by intraclass correlation coefficients (ICC), and sample size estimates were performed using effect sizes measured after INCS. RESULTS: NAC significantly induced acute increases in nasosorption tryptase and TNSS and reduced PNIF, and induced late increases in nasosorption IL-13 with sustained reductions in PNIF. Reproducibility across NACs varied for symptoms and biomarkers, with total tryptase 5 min post NAC having the highest reproducibility (ICC = 0.91). Treatment with INCS inhibited NAC-induced IL-13 while blunting changes in TNSS and PNIF. For a similar crossover study, 7 participants per treatment arm are needed to detect treatment effects comparable to INCS for TNSS. CONCLUSION: NAC-induced biomarkers and symptoms are reproducible and responsive to INCS. NAC is suitable for assessing pharmacodynamic activity and proof of mechanism for drugs targeting allergic inflammation.
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Asma , Rinitis Alérgica Estacional , Rinitis Alérgica , Humanos , Alérgenos , Rinitis Alérgica Estacional/diagnóstico , Rinitis Alérgica Estacional/tratamiento farmacológico , Interleucina-13 , Reproducibilidad de los Resultados , Triptasas , Estudios Cruzados , Rinitis Alérgica/diagnóstico , Rinitis Alérgica/tratamiento farmacológico , Corticoesteroides/uso terapéutico , Asma/tratamiento farmacológico , BiomarcadoresRESUMEN
BACKGROUND: The immune response in COVID-19 is characterized by the release of alarmin cytokines, which play crucial roles in immune activation and inflammation. The interplay between these cytokines and genetic variations may influence disease severity and outcomes, while sex differences might further contribute to variations in the immune response. METHODS: We measured the levels of alarmin cytokines in a cohort of COVID-19 and non-COVID-19 patients using a sensitive Meso Scale Discovery system. Additionally, we conducted an SNP analysis to identify genetic variations within the IL-33 and TSLP genes. The association between these genetic variations, cytokine production, and COVID-19 severity was examined. RESULTS: Our findings revealed elevated levels of IL-33 and IL-25 in COVID-19-positive patients compared to COVID-19-negative patients (p < 0.05), indicating their potential as therapeutic targets for disease modulation. Moreover, a minor allele within the IL-33 gene (rs3939286) was found to be associated with a protective effect against severe COVID-19 (p < 0.05), and minor alleles of the TSLP gene (rs2289276 and rs13806933) were found to significantly reduce TSLP protein levels in serum (p < 0.05). Sex-specific effects of TSLP and IL-33 SNPs were observed, suggesting a potential influence of sex hormones and genetic variations on the regulation of cytokine production. CONCLUSION: The present study highlights the importance of alarmin cytokines and genetic variations in COVID-19 severity, providing valuable insights into personalized treatment approaches. Our results suggest that targeting alarmin cytokines may offer potential therapeutic benefits in managing COVID-19. Furthermore, the sex-specific effects of genetic variations emphasize the need to consider individual genetic profiles and sex differences when designing targeted interventions.
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Asma , Eosinofilia Pulmonar , Humanos , Pramipexol , Asma/tratamiento farmacológico , Eosinófilos , Recuento de LeucocitosAsunto(s)
Asma , Hipersensibilidad Respiratoria , Humanos , Asma/genética , Células Epiteliales , Inmunidad InnataRESUMEN
BACKGROUND: Thymic stromal lymphopoietin (TSLP) is a key upstream regulator driving allergic inflammatory responses. We evaluated the efficacy and safety of ecleralimab, a potent inhaled neutralising antibody fragment against human TSLP, using allergen inhalation challenge (AIC) in subjects with mild atopic asthma. METHODS: This was a 12-week, randomised, double-blind, placebo-controlled, parallel-design, multicentre allergen bronchoprovocation study conducted at 10 centres across Canada and Germany. Subjects aged 18-60â years with stable mild atopic asthma were randomised (1:1) to receive 4â mg once-daily inhaled ecleralimab or placebo. Primary end-points were the allergen-induced change in forced expiratory volume in 1â s (FEV1) during the late asthmatic response (LAR) measured by area under the curve (AUC3-7h) and maximum percentage decrease (LAR%) on day 84, and the safety of ecleralimab. Allergen-induced early asthmatic response (EAR), sputum eosinophils and fractional exhaled nitric oxide (F ENO) were secondary and exploratory end-points. RESULTS: 28 subjects were randomised to ecleralimab (n=15) or placebo (n=13). On day 84, ecleralimab significantly attenuated LAR AUC3-7h by 64% (p=0.008), LAR% by 48% (p=0.029), and allergen-induced sputum eosinophils by 64% at 7â h (p=0.011) and by 52% at 24â h (p=0.047) post-challenge. Ecleralimab also numerically reduced EAR AUC0-2h (p=0.097) and EAR% (p=0.105). F ENO levels were significantly reduced from baseline throughout the study (p<0.05), except at 24â h post-allergen (day 43 and day 85). Overall, ecleralimab was safe and well tolerated. CONCLUSION: Ecleralimab significantly attenuated allergen-induced bronchoconstriction and airway inflammation, and was safe in subjects with mild atopic asthma.
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Asma , Hipersensibilidad Inmediata , Humanos , Administración por Inhalación , Alérgenos/efectos adversos , Pruebas de Provocación Bronquial , Estudios Cruzados , Citocinas , Método Doble Ciego , Volumen Espiratorio Forzado , Fragmentos de Inmunoglobulinas/uso terapéutico , Esputo , Linfopoyetina del Estroma Tímico , Adolescente , Adulto Joven , Adulto , Persona de Mediana EdadRESUMEN
Poorly controlled asthma can affect neonatal outcomes including congenital anomalies, which can be reduced with appropriate asthma care during pregnancy. Although there is a concern regarding the safety of asthma medication use during pregnancy and congenital anomalies, the risk of uncontrolled asthma outweighs any potential risks of controller and reliever medication use. Patient education before and during pregnancy is critical to ensure good compliance to therapy and reduce the risk of poor asthma control.
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Antiasmáticos , Asma , Complicaciones del Embarazo , Embarazo , Recién Nacido , Femenino , Humanos , Antiasmáticos/efectos adversos , Complicaciones del Embarazo/tratamiento farmacológico , Complicaciones del Embarazo/epidemiología , Asma/tratamiento farmacológico , Asma/epidemiologíaRESUMEN
The alarmin cytokines thymic stromal lymphopoietin (TSLP), interleukin (IL)-33, and IL-25 are epithelial cell-derived mediators that contribute to the pathobiology and pathophysiology of asthma. Released from airway epithelial cells exposed to environmental triggers, the alarmins drive airway inflammation through the release of predominantly T2 cytokines from multiple effector cells. The upstream positioning of the alarmins is an attractive pharmacological target to block multiple T2 pathways important in asthma. Blocking the function of TSLP inhibits allergen-induced responses including bronchoconstriction, airway hyperresponsiveness, and inflammation, and subsequent clinical trials of an anti-TSLP monoclonal antibody, tezepelumab, in asthma patients demonstrated improvements in lung function, airway responsiveness, inflammation, and importantly, a reduction in the rate of exacerbations. Notably, these improvements were observed in patients with T2-high and with T2-low asthma. Clinical trials blocking IL-33 and its receptor ST2 have also shown improvements in lung function and exacerbation rates; however, the impact of blocking the IL-33/ST2 axis in T2-high versus T2-low asthma is unclear. To date, there is no evidence that IL-25 blockade is beneficial in asthma. Despite the considerable overlap in the cellular functions of IL-25, IL-33, and TSLP, they appear to have distinct roles in the immunopathology of asthma.
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Asma , Citocinas , Humanos , Citocinas/metabolismo , Alarminas/uso terapéutico , Interleucina-33/metabolismo , Proteína 1 Similar al Receptor de Interleucina-1 , Linfopoyetina del Estroma Tímico , InflamaciónRESUMEN
Asthma is a chronic disease of the airways characterized by inflammation, tightened muscles, and thickened airway walls leading to symptoms such as shortness of breath, chest tightness, and cough in patients. The increased risk of asthma in children of asthmatics parents supports the existence of genetic factors involved in the pathogenesis of this disease. Genome-wide association studies have discovered several single nucleotide polymorphisms associated with asthma. These polymorphisms occur within several genes and can contribute to different asthma phenotypes, affect disease severity, and clinical response to different therapies. The complexity in the etiology of asthma also results from interactions between environmental and genetic factors. Environmental exposures have been shown to increase the prevalence of asthma in individuals who are genetically susceptible. This review summarizes what is currently known about the genetics of asthma in relation to risk, response to common treatments, and gene-environmental interactions.
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Asma , Estudio de Asociación del Genoma Completo , Humanos , Asma/genética , Asma/patología , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , EpitelioRESUMEN
The airway epithelium is the first line of defense for the lungs, detecting inhaled environmental threats through pattern recognition receptors expressed transmembrane or intracellularly. Activation of pattern recognition receptors triggers the release of alarmin cytokines IL-25, IL-33, and TSLP. These alarmins are important mediators of inflammation, with receptors widely expressed in structural cells as well as innate and adaptive immune cells. Many of the key effector cells in the allergic cascade also produce alarmins, thereby contributing to the airways disease by driving downstream type 2 inflammatory processes. Randomized controlled clinical trials have demonstrated benefit when blockade of TSLP and IL-33 were added to standard of care medications, suggesting these are important new targets for treatment of asthma. With genome-wide association studies demonstrating associations between single-nucleotide polymorphisms of the TSLP and IL-33 gene and risk of asthma, it will be important to understand which subsets of asthma patients will benefit most from anti-alarmin therapy.
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Alarminas , Asma , Células Epiteliales/metabolismo , Estudio de Asociación del Genoma Completo , Humanos , Interleucina-33/genética , Interleucina-33/metabolismoRESUMEN
BackgroundAdenovirus-vectored (Ad-vectored) vaccines are typically administered via i.m. injection to humans and are incapable of inducing respiratory mucosal immunity. However, aerosol delivery of Ad-vectored vaccines remains poorly characterized, and its ability to induce mucosal immunity in humans is unknown. This phase Ib trial evaluated the safety and immunogenicity of human serotype-5 Ad-vectored tuberculosis (TB) vaccine (AdHu5Ag85A) delivered to humans via inhaled aerosol or i.m. injection.MethodsThirty-one healthy, previously BCG-vaccinated adults were enrolled. AdHu5Ag85A was administered by single-dose aerosol using Aeroneb Solo Nebulizer or by i.m. injection. The study consisted of the low-dose (LD) aerosol, high-dose (HD) aerosol, and i.m. groups. The adverse events were assessed at various times after vaccination. Immunogenicity data were collected from the peripheral blood and bronchoalveolar lavage samples at baseline, as well as at select time points after vaccination.ResultsThe nebulized aerosol droplets were < 5.39 µm in size. Both LD and HD of AdHu5Ag85A administered by aerosol inhalation and i.m. injection were safe and well tolerated. Both aerosol doses, particularly LD, but not i.m., vaccination markedly induced airway tissue-resident memory CD4+ and CD8+ T cells of polyfunctionality. While as expected, i.m. vaccination induced Ag85A-specific T cell responses in the blood, the LD aerosol vaccination also elicited such T cells in the blood. Furthermore, the LD aerosol vaccination induced persisting transcriptional changes in alveolar macrophages.ConclusionInhaled aerosol delivery of Ad-vectored vaccine is a safe and superior way to elicit respiratory mucosal immunity. This study warrants further development of aerosol vaccine strategies against respiratory pathogens, including TB and COVID-19.Trial registrationClinicalTrial.gov, NCT02337270.FundingThe Canadian Institutes for Health Research (CIHR) and the Natural Sciences and Engineering Research Council of Canada funded this work.
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Aerosoles/farmacología , COVID-19/prevención & control , SARS-CoV-2/efectos de los fármacos , Vacunas contra la Tuberculosis/inmunología , Tuberculosis/prevención & control , Administración por Inhalación , Adolescente , Adulto , Aerosoles/administración & dosificación , Anticuerpos Neutralizantes/sangre , Vacuna BCG/inmunología , COVID-19/inmunología , Femenino , Humanos , Inmunidad Mucosa/efectos de los fármacos , Inmunidad Mucosa/inmunología , Masculino , Persona de Mediana Edad , Mycobacterium tuberculosis/inmunología , SARS-CoV-2/inmunología , SARS-CoV-2/patogenicidad , Tuberculosis/inmunología , Vacunación/métodos , Adulto JovenRESUMEN
The allergen provocation test is an established model of allergic airway diseases, including asthma and allergic rhinitis, allowing the study of allergen-induced changes in respiratory physiology and inflammatory mechanisms in sensitised individuals as well as their associations. In the upper airways, allergen challenge is focused on the clinical and pathophysiological sequelae of the early allergic response, and is applied both as a diagnostic tool and in research settings. In contrast, bronchial allergen challenge has almost exclusively served as a research tool in specialised research settings with a focus on the late asthmatic response and the underlying type 2 inflammation. The allergen-induced late asthmatic response is also characterised by prolonged airway narrowing, increased nonspecific airway hyperresponsiveness and features of airway remodelling including the small airways, and hence allows the study of several key mechanisms and features of asthma. In line with these characteristics, allergen challenge has served as a valued tool to study the cross-talk of the upper and lower airways and in proof-of-mechanism studies of drug development. In recent years, several new insights into respiratory phenotypes and endotypes including the involvement of the upper and small airways, innovative biomarker sampling methods and detection techniques, refined lung function testing as well as targeted treatment options further shaped the applicability of the allergen provocation test in precision medicine. These topics, along with descriptions of subject populations and safety, in line with the updated Global Initiative for Asthma 2021 document, will be addressed in this review.