ABSTRACT
BACKGROUND: Japanese guidelines recommend triple inhaled corticosteroid (ICS)/long-acting muscarinic antagonist (LAMA)/long-acting ß2-agonist (LABA) therapy in patients with chronic obstructive pulmonary disease (COPD) and no concurrent asthma diagnosis who experience frequent exacerbations and have blood eosinophil (EOS) count ≥ 300 cells/mm3, and in patients with COPD and asthma with continuing/worsening symptoms despite receiving dual ICS/LABA therapy. These post-hoc analyses of the KRONOS study in patients with COPD and without an asthma diagnosis, examine the effects of fixed-dose triple therapy with budesonide/glycopyrronium/formoterol fumarate dihydrate (BGF) versus dual therapies on lung function and exacerbations based on blood EOS count - focusing on blood EOS count 100 to < 300 cells/mm3 - as a function of exacerbation history and COPD severity. METHODS: In KRONOS, patients were randomized to receive treatments that included BGF 320/14.4/10 µg, glycopyrronium/formoterol fumarate dihydrate (GFF) 14.4/10 µg, or budesonide/formoterol fumarate dihydrate (BFF) 320/10 µg via metered dose inhaler (two inhalations twice-daily for 24 weeks). These post-hoc analyses assessed changes from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV1) over 12-24 weeks and moderate or severe COPD exacerbations rates over 24 weeks. The KRONOS study was not prospectively powered for these subgroup analyses. RESULTS: Among patients with blood EOS count 100 to < 300 cells/mm3, least squares mean treatment differences for lung function improvement favored BGF over BFF in patients without an exacerbation history in the past year and in patients with moderate and severe COPD, with observed differences ranging from 62 ml to 73 ml across populations. In this same blood EOS population, moderate or severe exacerbation rates were reduced for BGF relative to GFF by 56% in patients without an exacerbation history in the past year, by 47% in patients with moderate COPD, and by 50% in patients with severe COPD. CONCLUSIONS: These post-hoc analyses of patients with moderate-to-very severe COPD from the KRONOS study seem to indicate clinicians may want to consider a step-up to triple therapy in patients with persistent/worsening symptoms with blood EOS count > 100 cells/mm3, even if disease severity is moderate and there is no recent history of exacerbations. TRIAL REGISTRATION: ClinicalTrials.gov registry number NCT02497001 (registration date, 13 July 2015).
Subject(s)
Bronchodilator Agents , Budesonide , Eosinophils , Formoterol Fumarate , Glycopyrrolate , Pulmonary Disease, Chronic Obstructive , Humans , Male , Pulmonary Disease, Chronic Obstructive/drug therapy , Pulmonary Disease, Chronic Obstructive/physiopathology , Pulmonary Disease, Chronic Obstructive/blood , Pulmonary Disease, Chronic Obstructive/diagnosis , Glycopyrrolate/administration & dosage , Female , Aged , Middle Aged , Bronchodilator Agents/administration & dosage , Budesonide/administration & dosage , Eosinophils/drug effects , Formoterol Fumarate/administration & dosage , Double-Blind Method , Disease Progression , Lung/drug effects , Lung/physiopathology , Administration, Inhalation , Treatment Outcome , Muscarinic Antagonists/administration & dosage , Forced Expiratory Volume/drug effects , Forced Expiratory Volume/physiologyABSTRACT
Current treatments of eosinophilic chronic rhinosinusitis (ECRS) involve corticosteroids with various adverse effects and costly therapies such as dupilumab, highlighting the need for improved treatments. However, because of the lack of a proper mouse ECRS model that recapitulates human ECRS, molecular mechanisms underlying this disease are incompletely understood. ECRS is often associated with aspirin-induced asthma, suggesting that dysregulation of lipid mediators in the nasal mucosa may underlie ECRS pathology. We herein found that the expression of microsomal PGE synthase-1 (encoded by PTGES) was significantly lower in the nasal mucosa of ECRS patients than that of non-ECRS subjects. Histological, transcriptional, and lipidomics analyses of Ptges-deficient mice revealed that defective PGE2 biosynthesis facilitated eosinophil recruitment into the nasal mucosa, elevated expression of type-2 cytokines and chemokines, and increased pro-allergic and decreased anti-allergic lipid mediators following challenges with Aspergillus protease and ovalbumin. A nasal spray containing agonists for the PGE2 receptor EP2 or EP4, including omidenepag isopropyl that has been clinically used for treatment of glaucoma, markedly reduced intranasal eosinophil infiltration in Ptges-deficient mice. These results suggest that the present model using Ptges-deficient mice is more relevant to human ECRS than are previously reported models and that eosinophilic inflammation in the nasal mucosa can be efficiently blocked by activation of the PGE2-EP2 pathway. Furthermore, our findings suggest that drug repositioning of omidenepag isopropyl may be useful for treatment of patients with ECRS.
Subject(s)
Dinoprostone , Eosinophilia , Mice, Knockout , Nasal Mucosa , Receptors, Prostaglandin E, EP2 Subtype , Rhinitis , Sinusitis , Animals , Sinusitis/drug therapy , Sinusitis/metabolism , Sinusitis/immunology , Humans , Mice , Rhinitis/drug therapy , Rhinitis/metabolism , Rhinitis/immunology , Dinoprostone/metabolism , Nasal Mucosa/metabolism , Nasal Mucosa/immunology , Nasal Mucosa/drug effects , Eosinophilia/drug therapy , Eosinophilia/metabolism , Receptors, Prostaglandin E, EP2 Subtype/metabolism , Disease Models, Animal , Male , Signal Transduction/drug effects , Prostaglandin-E Synthases/genetics , Prostaglandin-E Synthases/metabolism , Eosinophils/immunology , Eosinophils/metabolism , Eosinophils/drug effects , Female , Chronic Disease , Mice, Inbred C57BL , RhinosinusitisABSTRACT
Polystyrene microplastics (PS-MP) and dibutyl phthalate (DBP) are plastic pollution derivatives (PPDs) commonly found in the natural environment. To investigate the effects of PPD exposure on the risk of allergic asthma, we established a PPD exposure group in a mouse model. The dose administered for PS-MP was 0.1 mg/d and for DBP was 30 mg/kg/d, with a 5-week oral administration period. The pathological changes of airway tissue and the increase of oxidative stress and inflammatory response confirmed that PPD aggravated eosinophilic allergic asthma in mice. The mitochondrial morphological changes and metabolomics of mice confirmed that ferrotosis and oxidative stress played key roles in this process. Treatment with 100 mg/Kg deferoxamine (DFO) provided significant relief, and metabolomic analysis of lung tissue supported the molecular toxicological. Our findings suggest that the increased levels of reactive oxygen species (ROS) in the lungs lead to Th2-mediated eosinophilic inflammation, characterized by elevated IL-4, IL-5, and eosinophils, and reduced INF-γ levels. This inflammatory response is mediated by the NFκB pathway and exacerbates type I hypersensitivity through increased IL-4 production. In this study, the molecular mechanism by which PPD aggravates asthma in mice was elucidated, which helps to improve the understanding of the health effects of PPD and lays a theoretical foundation for addressing the health risks posed by PPD.
Subject(s)
Asthma , Ferroptosis , Lung , Metabolomics , Animals , Asthma/chemically induced , Mice , Lung/drug effects , Lung/pathology , Ferroptosis/drug effects , Dibutyl Phthalate/toxicity , Th2 Cells/immunology , Oxidative Stress , Environmental Pollutants/toxicity , Microplastics/toxicity , Eosinophils/drug effects , Plastics/toxicityABSTRACT
BACKGROUND: Previous studies have reported reduced acute exacerbation rates and improved symptom control in asthma patients treated using inhaled corticosteroids plus formoterol maintenance and reliever therapy (MART). Fluticasone furoate (FF) and vilanterol (VIL) also provide rapid bronchodilation and sustained anti-inflammatory effects, however no studies have investigated FF/VIL as MART for asthma control. METHODS: From October 1, 2021 to September 30, 2023, this retrospective study included asthma patients classified as step 3 or 4 according to the Global Initiative for Asthma guidelines, who were then divided into two groups. One group received BUD/FOR as MART, while the other received FF/VIL as MART. Pulmonary function tests, exacerbation rates, Asthma Control Test (ACT), fractional exhaled nitric oxide (FeNO) levels, and blood eosinophil counts were measured before and after 12 months of treatment. RESULTS: A total of 161 patients were included, of whom 36 received BUD/FOR twice daily as MART, and 125 received FF/VIL once daily as MART. After 12 months of treatment, the FF/VIL group showed a significant increase in ACT scores by 1.57 (p < 0.001), while the BUD/FOR group had an increase of 0.88 (p = 0.11). In terms of FeNO levels, the BUD/FOR group experienced a decline of -0.2 ppb (p = 0.98), whereas the FF/VIL group had a mild increase of + 0.8 ppb (p = 0.7). Notably, there was a significant difference in the change of FeNO between the two groups (∆ FeNO: -0.2 ppb in BUD/FOR; + 0.8 ppb in FF/VIL, p < 0.001). There were no significant alterations observed in FEV1, blood eosinophil count, or acute exacerbation decline in either group. CONCLUSIONS: In the current study, patients treated with FF/VIL as MART showed improvements in ACT scores, while those treated with BUD/FOR as MART exhibited a reduction in FeNO levels. However, the difference between the two treatment groups did not reach clinical significance. Thus, FF/VIL as MART showed similar effectiveness to BUD/FOR as MART.
Subject(s)
Asthma , Benzyl Alcohols , Chlorobenzenes , Drug Combinations , Humans , Male , Female , Benzyl Alcohols/administration & dosage , Benzyl Alcohols/therapeutic use , Retrospective Studies , Asthma/drug therapy , Middle Aged , Chlorobenzenes/administration & dosage , Chlorobenzenes/therapeutic use , Adult , Bronchodilator Agents/administration & dosage , Bronchodilator Agents/therapeutic use , Administration, Inhalation , Androstadienes/administration & dosage , Androstadienes/therapeutic use , Budesonide/administration & dosage , Budesonide/therapeutic use , Anti-Asthmatic Agents/therapeutic use , Anti-Asthmatic Agents/administration & dosage , Aged , Formoterol Fumarate/administration & dosage , Treatment Outcome , Nitric Oxide/analysis , Nitric Oxide/metabolism , Budesonide, Formoterol Fumarate Drug Combination/administration & dosage , Budesonide, Formoterol Fumarate Drug Combination/therapeutic use , Respiratory Function Tests , Eosinophils/drug effectsABSTRACT
Atopic dermatitis (AD) is a chronic, allergic inflammatory skin disorder that lacks a definite cure. Using a mouse DNCB-induced AD-like skin lesions model, this study evaluated the potential therapeutic utility of tHGA as an oral and topical treatment for AD. Male BALB/c mice were sensitised and challenged with 1% and 0.5% DNCB on their shaved dorsal skin. Mice in the treatment group were administered tHGA (20, 40, and 80 mg/kg) orally three times per week for 2 weeks, or tHGA (0.2%, 1%, and 5%) topically once daily for 12 days. On day 34, the mice were euthanized, and blood and dorsal skin samples were obtained for analysis. All doses of orally and topically administered tHGA significantly improved scratching, epidermal thickness, blood eosinophilia and mast cell infiltration. There was a minor discrepancy between the two routes of administration, with orally treated tHGA showing significant reductions in Scoring of Atopic Dermatitis (SCORAD), tissue eosinophil infiltration, serum IgE and skin IL-4 levels with treatment of 40 and 80 mg/kg tHGA, whereas topically applied tHGA showed significant reductions in all dosages. These findings suggest that tHGA exhibited therapeutic potential for AD as both oral and topical treatment ameliorates AD-like symptoms in the murine model.
Subject(s)
Administration, Topical , Dermatitis, Atopic , Dinitrochlorobenzene , Immunoglobulin E , Mice, Inbred BALB C , Skin , Animals , Dermatitis, Atopic/drug therapy , Dermatitis, Atopic/chemically induced , Dermatitis, Atopic/pathology , Administration, Oral , Male , Mice , Immunoglobulin E/blood , Skin/drug effects , Skin/pathology , Skin/metabolism , Disease Models, Animal , Acetophenones/administration & dosage , Acetophenones/pharmacology , Acetophenones/therapeutic use , Eosinophils/drug effects , Interleukin-4/metabolism , Mast Cells/drug effectsABSTRACT
BACKGROUND: We aim to investigate the effect of YiQi GuBen formula (YQGB) on airway inflammation and airway remodeling in the ovalbumin (OVA)-induced asthma model to further explore the potential mechanisms of YQGB in treating allergic asthma. METHODS: Mice were divided into five groups randomly (n = 10): the control group, OVA group, OVA + Dex (0.1 mg/kg) group, OVA + low-dose (1.1 g/kg) YQGB group, and OVA + high-dose (2.2 g/kg) YQGB group. Inflammatory cell count and IgE were detected in bronchoalveolar lavage fluid (BALF). Lung tissue histopathology was observed by using H&E, PAS, Masson, and immunohistochemistry staining. qRT-PCR and western blot were applied to analyze key genes and proteins associated with TLR4 and NF-κB signaling pathways. RESULTS: In OVA-induced asthma mice, YQGB decreased eosinophils and IgE in BALF. YQGB alleviated the OVA-induced inflammatory infiltration and declined IL-4, IL-5, IL-13, Eotaxin, ECP, GM-CSF, LTC4, and LTD4. YQGB attenuated the OVA-induced goblet cell metaplasia and mucus hypersecretion. YQGB mitigated the OVA-induced subepithelial fibrosis and lowered TGF-ß1, E-Cadherin, Vimentin, and Fibronectin. YQGB ameliorated the OVA-induced airway smooth muscle thickening and lessened α-SMA and PDGF levels. YQGB reduced the expression of TLR4, MyD88, TRAF6, IκBα, and p65 mRNAs, and IκBα and p-p65 protein levels were also reduced. CONCLUSION: YQGB exhibits the anti-asthma effect by reducing airway inflammation and airway remodeling through suppressing TLR4/NF-κB signaling pathway, and is worth promoting clinically.
Subject(s)
Airway Remodeling , Asthma , Bronchoalveolar Lavage Fluid , Disease Models, Animal , Drugs, Chinese Herbal , Mice, Inbred BALB C , NF-kappa B , Ovalbumin , Signal Transduction , Toll-Like Receptor 4 , Animals , Asthma/drug therapy , Asthma/chemically induced , Toll-Like Receptor 4/metabolism , Airway Remodeling/drug effects , Signal Transduction/drug effects , NF-kappa B/metabolism , Drugs, Chinese Herbal/pharmacology , Mice , Immunoglobulin E/blood , Lung/drug effects , Lung/pathology , Lung/metabolism , Female , Inflammation/drug therapy , Eosinophils/drug effects , Eosinophils/metabolism , Anti-Asthmatic Agents/pharmacology , Cytokines/metabolismABSTRACT
BACKGROUND: The phenotyping of chronic obstructive pulmonary disease (COPD) has increasingly gained attention in recent years, as it leads to new and individualized therapeutic concepts. OBJECTIVE: The aim is to provide an overview of the heterogeneity of COPD and to summarize current drug therapy concepts, particularly in the context of eosinophilic airway inflammation. DATA: Several prospective, randomized, placebo-controlled studies have shown a reduction in exacerbations and overall mortality with inhaled triple therapy using an inhaled corticosteroid and dual bronchodilation. The higher the eosinophils in the blood, the greater the expected effect. In addition, a reduction in exacerbations with biologics in COPD with eosinophilia has been demonstrated for dupilumab. Eosinophil-guided therapy for acute exacerbations is the subject of current research. CONCLUSION: For COPD without exacerbations, dual bronchodilation forms the basis of inhaled therapy. With exacerbations, inhaled triple therapy is indicated for patients with a blood eosinophil count of ≥â¯300/µl. This type of treatment may also be useful when eosinophils are between 100 and 300/µl. Therapy with dupilumab is a possible option for the eosinophilic phenotype in the near future.
Subject(s)
Antibodies, Monoclonal, Humanized , Bronchodilator Agents , Eosinophilia , Pulmonary Disease, Chronic Obstructive , Pulmonary Disease, Chronic Obstructive/drug therapy , Humans , Eosinophilia/drug therapy , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/administration & dosage , Bronchodilator Agents/therapeutic use , Bronchodilator Agents/administration & dosage , Administration, Inhalation , Eosinophils/drug effects , Eosinophils/metabolism , Adrenal Cortex Hormones/therapeutic use , Adrenal Cortex Hormones/administration & dosage , Drug Therapy, Combination , Randomized Controlled Trials as Topic , Pulmonary Eosinophilia/drug therapyABSTRACT
AIMS: Benralizumab, a humanized, afucosylated monoclonal antibody against the interleukin 5 receptor, α subunit, causes rapid depletion of eosinophils by antibody-dependent cellular cytotoxicity. We investigated the pharmacokinetic and pharmacodynamic effects of benralizumab in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) from the phase III OSTRO trial. METHODS: Patients received a placebo or 30 mg of benralizumab by subcutaneous injection every 8 weeks (first three doses every 4 weeks) to week 48; a subset of patients continued in an extended follow-up period to assess treatment durability to week 80. Serum benralizumab concentrations and blood eosinophil and basophil counts were assessed to week 80. Biomarker assessments were performed on nasal polyp tissue biopsies at week 56 and nasal lining fluid at weeks 24 and 56 to examine changes in immune cells and inflammatory mediators. RESULTS: Among 185 patients in this analysis, 93 received benralizumab. Serum benralizumab concentrations reached a steady state by week 24 (median concentration 385.52 ng mL-1); blood eosinophils were almost fully depleted and blood basophils were reduced between weeks 16 and 56. Nasal polyp tissue eosinophils decreased with benralizumab from 57.6 cells mm-2 at baseline to 0 cells mm-2 at week 56 (P < .001 vs placebo), and tissue mast cells were numerically reduced. In nasal lining fluid, eosinophil-derived neurotoxin was significantly reduced at weeks 24 and 56 (P < .001) and interleukin-17 at week 56 (P < .05) with benralizumab. CONCLUSION: Benralizumab treatment led to rapid, sustained, nearly complete depletion of eosinophils from blood and nasal polyp tissue in patients with CRSwNP.
Subject(s)
Antibodies, Monoclonal, Humanized , Eosinophils , Nasal Polyps , Rhinitis , Sinusitis , Humans , Nasal Polyps/drug therapy , Nasal Polyps/complications , Antibodies, Monoclonal, Humanized/pharmacokinetics , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Monoclonal, Humanized/administration & dosage , Sinusitis/drug therapy , Sinusitis/complications , Male , Chronic Disease , Female , Rhinitis/drug therapy , Middle Aged , Adult , Eosinophils/drug effects , Double-Blind Method , Basophils/drug effects , Aged , Leukocyte Count , Injections, Subcutaneous , Treatment Outcome , RhinosinusitisABSTRACT
OBJECTIVE: SHR-1703 is a novel humanized IgG1 monoclonal antibody with high IL-5 affinity and prolonged half-life, aiming to control eosinophil-related diseases. The study intended to evaluate pharmacokinetics, pharmacodynamics, immunogenicity, safety, and tolerability of SHR-1703 in healthy subjects. METHODS: A single-center, randomized, double-blind, placebo-controlled, single-dose escalation phase I study was conducted. 42 subjects were allocated to sequentially receive single subcutaneous injection of 20, 75, 150, 300, and 400 mg SHR-1703 or placebo. RESULTS: After administration, SHR-1703 was slowly absorbed with median Tmax ranging from 8.5 to 24.5 days. Mean t1/2 in 150 to 400 mg doses was 86 to 100 days. Cmax and AUC increased in nearly dose-proportional pattern over range of 75 to 400 mg SHR-1703. After receiving SHR-1703, peripheral blood eosinophils (EOS) greatly decreased from baseline, which showed no significant change from baseline in placebo group. Magnitude and duration of reduction of EOS rose with increased dosing of SHR-1703. In 400 mg dose, remarkable efficacy of reducing EOS maintained up to approximately 6 months post single administration. Moreover, SHR-1703 exhibited low immunogenicity (2.9%), favorable safety, and tolerability in healthy subjects. CONCLUSION: Pharmacokinetics, pharmacodynamics, immunogenicity, safety, and tolerability of SHR-1703 support further clinical development of SHR-1703 in eosinophil-associated diseases. CLINICAL TRIAL REGISTRATION: The study was registered on the ClinicalTrials.gov (identifier: NCT04480762).
Subject(s)
Antibodies, Monoclonal, Humanized , Dose-Response Relationship, Drug , Eosinophils , Interleukin-5 , Humans , Double-Blind Method , Male , Adult , Female , Eosinophils/drug effects , Young Adult , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/pharmacokinetics , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/pharmacology , Interleukin-5/antagonists & inhibitors , Interleukin-5/immunology , Half-Life , Injections, Subcutaneous , Middle Aged , Area Under Curve , Healthy VolunteersABSTRACT
Introduction: This work was to explore the efficacy and safety of self-made WenyangJianpi-qushi Decoction plus mometasone furoate cream in atopic dermatitis (AD) of spleen deficiency and dampness accumulation type. Material and method: 120 patients with this kind of atopic dermatitis were grouped: The Observation group (disease health education + basic treatment + mometasone furoate cream + self-made Decoction) and The Control group (disease health education + basic treatment + mometasone furoate cream), 60 cases in each group. The SCORAD score, serum IgE level, peripheral blood eosinophils, adverse events, recurrence rate, and total effective rate after treatment were observed.Result: Through treatment, SCORAD score of the observation group (29.96 ± 2.88) was lower as against controls (36.04 ± 3.12), p < 0.05. Through treatment, the peripheral blood eosinophil count in the observation group was (311.26 ± 50.19) 106/L, which was lower than (582.71 ± 54.75) 106/L in controls; the serum lgE of the observation group was (712.44 ± 93.32) IU/mL, which was lower than the controls (890.12 ± 81.25) IU/mL, p < 0.05. The Observation group (56/60, 93.33%) demonstrated superior total effective rate to the controls (34/60, 56.67%); The recurrence rate of the observation group was 4/60 (6.67%), which was lower than the controls 16/60 (26.67%), p < 0.05.Conclusion: Self-made WenyangJianpi-qushi Decoction plus mometasone furoate cream to treat atopic dermatitis of spleen deficiency and dampness accumulation type has significant efficacy and good safety.
Subject(s)
Dermatitis, Atopic , Drugs, Chinese Herbal , Mometasone Furoate , Dermatitis, Atopic/drug therapy , Humans , Mometasone Furoate/therapeutic use , Mometasone Furoate/administration & dosage , Male , Female , Drugs, Chinese Herbal/therapeutic use , Drugs, Chinese Herbal/adverse effects , Drugs, Chinese Herbal/administration & dosage , Adult , Adolescent , Young Adult , Eosinophils/drug effects , Spleen/drug effects , Spleen/pathology , Middle Aged , Immunoglobulin E/blood , Child , Drug Therapy, Combination , Treatment Outcome , Skin Cream/therapeutic useABSTRACT
Eosinophils are important immune effector cells that affect Tâ cell-mediated antitumor immunity. However, the low frequency and restrained activity of eosinophils restricted the outcome of cancer immunotherapies. We herein report an eosinophil-activating semiconducting polymer nanoparticle (SPNe) to improve photodynamic tumor immunogenicity, modulate eosinophil chemotaxis, and reinvigorate T-cell immunity for activated cancer photo-immunotherapy. SPNe comprises an amphiphilic semiconducting polymer and a dipeptidyl peptidase 4 (DPP4) inhibitor sitagliptin via a 1O2-cleavable thioketal linker. Upon localized NIR photoirradiation, SPNe generates 1O2 to elicit immunogenic cell death of tumors and induce specific activation of sitagliptin. The subsequent inhibition of DPP4 increases intratumoral CCL11 levels to promote eosinophil chemotaxis and activation. SPNe-mediated photo-immunotherapy synergized with immune checkpoint blockade greatly promotes tumor infiltration and activation of both eosinophils and Tâ cells, effectively inhibiting tumor growth and metastasis. Thus, this study presents a generic polymeric nanoplatform to modulate specific immune cells for precision cancer immunotherapy.
Subject(s)
Eosinophils , Immunotherapy , Nanoparticles , Polymers , Nanoparticles/chemistry , Polymers/chemistry , Polymers/pharmacology , Mice , Animals , Eosinophils/drug effects , Eosinophils/metabolism , Eosinophils/immunology , Semiconductors , Humans , Neoplasms/drug therapy , Neoplasms/therapy , Neoplasms/pathology , Photochemotherapy , Cell Line, Tumor , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacologyABSTRACT
BACKGROUND: Long-term tezepelumab treatment in the DESTINATION study (NCT03706079) resulted in reduced asthma exacerbations, reduced biomarker levels, and improved lung function and symptom control in patients with severe, uncontrolled asthma. OBJECTIVE: To explore the time course of changes in biomarkers and clinical manifestations after treatment cessation after 2 years of tezepelumab treatment. METHODS: DESTINATION was a 2-year, phase 3, multicenter, randomized, placebo-controlled, double-blind study of tezepelumab treatment in patients (12-80 years old) with severe asthma. Patients received their last treatment doses at week 100 and could enroll in an extended follow-up period from weeks 104 to 140. Change over time in key biomarkers and clinical outcomes were assessed in tezepelumab vs placebo recipients for 40 weeks after stopping treatment. RESULTS: Of 569 patients enrolled in the extended follow-up period, 426 were included in the analysis (289 received tezepelumab and 137 placebo). In the 40-week period after the last tezepelumab dose, blood eosinophil counts, fractional exhaled nitric oxide levels, and Asthma Control Questionnaire-6 scores gradually increased from weeks 4 to 10, with a gradual reduction in pre-bronchodilator forced expiratory volume in 1 second such that blood eosinophil counts, fractional exhaled nitric oxide levels, and clinical outcomes returned to placebo levels; however, none of these outcomes returned to baseline levels. Total IgE levels increased later from week 28 and remained well below placebo and baseline levels during the 40-week period after the last tezepelumab dose. CONCLUSION: This analysis reveals the benefits of continued tezepelumab treatment in the management of patients with severe, uncontrolled asthma, compared with stopping treatment after 2 years. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03706079.
Subject(s)
Anti-Asthmatic Agents , Antibodies, Monoclonal, Humanized , Asthma , Biomarkers , Humans , Asthma/drug therapy , Middle Aged , Male , Female , Adult , Anti-Asthmatic Agents/therapeutic use , Anti-Asthmatic Agents/administration & dosage , Aged , Follow-Up Studies , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/administration & dosage , Double-Blind Method , Treatment Outcome , Adolescent , Aged, 80 and over , Young Adult , Child , Immunoglobulin E/blood , Eosinophils/immunology , Eosinophils/drug effectsABSTRACT
RATIONALE: Diesel engine exhaust (DEE) is associated with the development and exacerbation of asthma. Studies have shown that DEE can aggravate allergen-induced eosinophilic inflammation in lung. However, it remains not clear that whether DEE alone could initiate non-allergic eosinophilic inflammation and airway hyperresponsiveness (AHR) through innate lymphoid cells (ILCs) pathway. OBJECTIVE: This study aims to investigate the airway inflammation and hyperresponsiveness and its relationship with ILC after DEE exposure. METHOD: Non-sensitized BALB/c mice were exposed in the chamber of diesel exhaust or filtered air for 2, 4, and 6 weeks (4â¯h/day, 6 days/week). Anti-CD4 mAb or anti-Thy1.2 mAb was administered by intraperitoneal injection to inhibit CD4+T or ILCs respectively. AHRãairway inflammation and ILCs were assessed. RESULT: DEE exposure induced significantly elevated level of neutrophils, eosinophils, collagen content at 4, 6 weeks. Importantly, the airway AHR was only significant in the 4weeks-DEE exposure group. No difference of the functional proportions of Th2 cells was found between exposure group and control group. The proportions of IL-5+ILC2, IL-17+ILC significantly increased in 2, 4weeks-DEE exposure group. After depletion of CD4+T cells, both the proportion of IL-5+ILC2 and IL-17A ILCs was higher in the 4weeks-DEE exposure group which induced AHR, neutrophilic and eosinophilic inflammation accompanied by the IL-5, IL-17A levels. CONCLUSION: Diesel engine exhaust alone can imitate asthmatic characteristics in mice model. Lung-resident ILCs are one of the major effectors cells responsible for a mixed Th2/Th17 response and AHR.
Subject(s)
Air Pollutants , Lymphocytes , Mice, Inbred BALB C , Vehicle Emissions , Animals , Vehicle Emissions/toxicity , Mice , Lymphocytes/drug effects , Lymphocytes/immunology , Air Pollutants/toxicity , Inflammation/chemically induced , Eosinophils/immunology , Eosinophils/drug effects , Respiratory Hypersensitivity/immunology , Respiratory Hypersensitivity/chemically induced , Female , Bronchoalveolar Lavage Fluid/cytology , Bronchoalveolar Lavage Fluid/immunology , MaleSubject(s)
Antibodies, Monoclonal, Humanized , Asthma , Eosinophils , Sputum , Humans , Antibodies, Monoclonal, Humanized/therapeutic use , Eosinophils/immunology , Eosinophils/drug effects , Sputum/cytology , Sputum/immunology , Asthma/drug therapy , Asthma/immunology , Male , Female , Anti-Asthmatic Agents/therapeutic use , Anti-Asthmatic Agents/pharmacology , Middle Aged , Adult , Leukocyte Count , Treatment OutcomeABSTRACT
INTRODUCTION: Asthma encompasses a spectrum of phenotypes often categorized into two groups- type 2 high (T2 high) and type 2 low (T2 low). T2 high includes atopic and eosinophilic presentations whereas T2 low is non-atopic, non-eosinophilic, and oft associated with neutrophilic inflammation. Eosinophilic asthma is often driven by IgE, IL-4, IL-5, and IL-13 and TSLP. This can lead to eosinophilic inflammatory response in the airways which in turn can be used as target for treatment. AREAS COVERED: The article will focus on biologic therapy that is currently being used in eosinophilic asthma management in mainly the adult population including clinical trials and co-morbidities that can be treated using the same biologics. A review on asthma biologics for pediatric population has been reviewed elsewhere. EXPERT OPINION: Biological therapy for asthma targeting the IgE, IL-4, IL-5, IL-13, and TSLP pathways are shown to have benefit for the treatment of eosinophilic asthma, as exemplified in real-world studies. When choosing the right biological agent factors such as phenotype, comorbidities, and cost-effectiveness of the biologic agent must be taken into consideration.
Subject(s)
Asthma , Biological Therapy , Humans , Asthma/drug therapy , Asthma/immunology , Eosinophilia/immunology , Eosinophilia/drug therapy , Anti-Asthmatic Agents/therapeutic use , Immunoglobulin E/immunology , Biological Products/therapeutic use , Eosinophils/immunology , Eosinophils/drug effects , Eosinophils/metabolism , Cytokines/immunology , Cytokines/antagonists & inhibitors , Cytokines/metabolismABSTRACT
BACKGROUND: Eosinophils and basophils are implicated in allergic reactions, and the molecule CD200 on B cells may have regulatory functions. Assessing the associations between the expression of CD200 on B lymphocytes and eosinophils and basophils helps unravel the complex immune interactions in atopic dermatitis, aiding in targeted therapeutic approaches. OBJECTIVE: The aim of our study is to evaluate the association between the count of eosinophils, basophils, CD16+ eosinophils, CD203+ basophils, the expression of activation marker CD200 on B cells and on their subsets in patients suffering from atopic dermatitis with and without dupilumab and in control group. MATERIALS AND METHODS: Altogether we examined 75 subjects: 45 patients suffering from atopic dermatitis -32 patients without dupilumab treatment, 13 patients with dupilumab treatment and 30 subjects as a control group. Immunophenotype was examined by flow cytometry in which monoclonal antibodies with fluorescent molecules were used. For statistical analysis we used non-parametric Kruskal-Wallis one-factor analysis of variance with post-hoc by Dunn's test with Bonferroni modification and the Spearman's rank correlation coefficient with calculation of R2 (%, percent of Variation Explained). RESULTS: In patients with dupilumab therapy we confirmed the association between absolute eosinophils and expression of molecule CD200 on total B lymphocytes (in 23.9 %), non-switched (in 27.2 %), naive (in 25 %) and memory (in 20.3 %) B lymphocytes and between relative eosinophils and expression of CD200 on total B lymphocytes (in 22.8 % %), non-switched (in 29 %), naive (in 21.3 %) and memory (in 22.3 %) B lymphocytes. This association is low in AD patients without dupilumab and even non linear in control healthy subjects. CONCLUSION: The higher association between eosinophils and expression of CD200 molecule on memory, naive and non switched B lymphocytes in AD patients under dupilumab therapy suggests that activation of B lymphocytes is caused by IL-4, whose production involves eosinophils and the CD200 molecule on B lymphocytes.
Subject(s)
Antibodies, Monoclonal, Humanized , Antigens, CD , B-Lymphocytes , Basophils , Dermatitis, Atopic , Eosinophils , Humans , Dermatitis, Atopic/immunology , Dermatitis, Atopic/drug therapy , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/pharmacology , Basophils/immunology , Eosinophils/immunology , Eosinophils/drug effects , Male , Female , Adult , Antigens, CD/metabolism , Antigens, CD/immunology , Pilot Projects , B-Lymphocytes/immunology , B-Lymphocytes/drug effects , Middle Aged , Young Adult , Leukocyte CountABSTRACT
Bruton's Tyrosine kinase (BTK) plays a pivotal role as the key mediator in B cell signaling. Recent research has revealed that it is also expressed in cells critical to asthma development, such as T cells, and eosinophils. This study aims to investigate the potential of BTK inhibitor in eosinophilic asthma mouse model. BALB/c mice were sensitized with ovalbumin (OVA) via intraperitoneal injections and followed by OVA nebulizations. The mice were treated with 250 µg/ml or 500 µg/ml of ibrutinib before the second intraperitoneal injection and the first nebulization. Two days after the last OVA challenge, airway hyperresponsiveness (AHR) was assessed with methacholine, and differential cell count in bronchoalveolar lavage fluid (BALF) was performed. The cytokines were measured in BALF, and serum OVA-specific IgE and IgG antibody levels were evaluated by ELISA. The inhibitory effect of ibrutinib was also evaluated in splenic mononuclear cells, mast cells, eosinophils, and T cells in vitro. Treatment with ibrutinib significantly attenuated AHR and airway inflammation, compared to the OVA-induced positive control. The treatment also reduced IL-4, IL-5, IL-13 and IFN-γ cytokine levels and suppressed OVA-specific IgE and IgG production compared to the OVA-induced positive control. Additionally, ibrutinib decreased beta-hexosaminidase release from mast cells, type 2 cytokine productions from mononuclear cells and T cells, and eosinophilic activation markers in vitro. The results of this study suggest that ibrutinib treatment could exert anti-allergic effects by inactivating B cells and other BTK-expressing cells. Further studies are needed to investigate the potential therapeutic effect of ibrutinib on allergic diseases.
Subject(s)
Adenine , Adenine/analogs & derivatives , Agammaglobulinaemia Tyrosine Kinase , Asthma , Cytokines , Disease Models, Animal , Eosinophils , Immunoglobulin E , Mice, Inbred BALB C , Ovalbumin , Piperidines , Protein Kinase Inhibitors , Animals , Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Asthma/drug therapy , Asthma/immunology , Piperidines/therapeutic use , Piperidines/pharmacology , Ovalbumin/immunology , Adenine/therapeutic use , Adenine/pharmacology , Immunoglobulin E/blood , Immunoglobulin E/immunology , Cytokines/metabolism , Eosinophils/immunology , Eosinophils/drug effects , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Mice , Pyrimidines/therapeutic use , Pyrimidines/pharmacology , Female , Pyrazoles/therapeutic use , Pyrazoles/pharmacology , Bronchoalveolar Lavage Fluid/cytology , Bronchoalveolar Lavage Fluid/immunology , Immunoglobulin G/blood , Anti-Asthmatic Agents/therapeutic use , Anti-Asthmatic Agents/pharmacology , Cells, Cultured , Humans , Mast Cells/drug effects , Mast Cells/immunologyABSTRACT
OBJECTIVE: Angiotensin-(1-7) [Ang-(1-7)] is a pro-resolving mediator. It is not known whether the pro-resolving effects of Ang-(1-7) are sustained and protect the lung from a subsequent inflammatory challenge. This study sought to investigate the impact of treatment in face of a second allergic or lipopolysaccharide (LPS) challenge. METHODS: Mice, sensitized and challenged with ovalbumin (OVA), received a single Ang-(1-7) dose at the peak of eosinophilic inflammation, 24 h after the final OVA challenge. Subsequently, mice were euthanized at 48, 72, 96, and 120 h following the OVA challenge, and cellular infiltrate, inflammatory mediators, lung histopathology, and macrophage-mediated efferocytic activity were evaluated. The secondary inflammatory stimulus (OVA or LPS) was administered 120 h after the last OVA challenge, and subsequent inflammatory analyses were performed. RESULTS: Treatment with Ang-(1-7) resulted in elevated levels of IL-10, CD4+Foxp3+, Mres in the lungs and enhanced macrophage-mediated efferocytic capacity. Moreover, in allergic mice treated with Ang-(1-7) and then subjected to a secondary OVA challenge, inflammation was also reduced. Similarly, in mice exposed to LPS, Ang-(1-7) effectively prevented the lung inflammation. CONCLUSION: A single dose of Ang-(1-7) resolves lung inflammation and protect the lung from a subsequent inflammatory challenge highlighting its potential therapeutic for individuals with asthma.