Background Short-term targeted treatment can potentially prevent fall asthma exacerbations while limiting therapy exposure. Objective We sought to compare (1) omalizumab with placebo and (2) ...omalizumab with an inhaled corticosteroid (ICS) boost with regard to fall exacerbation rates when initiated 4 to 6 weeks before return to school. Methods A 3-arm, randomized, double-blind, double placebo-controlled, multicenter clinical trial was conducted among inner-city asthmatic children aged 6 to 17 years with 1 or more recent exacerbations ( clincaltrials.gov # NCT01430403 ). Guidelines-based therapy was continued over a 4- to 9-month run-in phase and a 4-month intervention phase. In a subset the effects of omalizumab on IFN-α responses to rhinovirus in PBMCs were examined. Results Before the falls of 2012 and 2013, 727 children were enrolled, 513 were randomized, and 478 were analyzed. The fall exacerbation rate was significantly lower in the omalizumab versus placebo arms (11.3% vs 21.0%; odds ratio OR, 0.48; 95% CI, 0.25-0.92), but there was no significant difference between omalizumab and ICS boost (8.4% vs 11.1%; OR, 0.73; 95% CI, 0.33-1.64). In a prespecified subgroup analysis, among participants with an exacerbation during the run-in phase, omalizumab was significantly more efficacious than both placebo (6.4% vs 36.3%; OR, 0.12; 95% CI, 0.02-0.64) and ICS boost (2.0% vs 27.8%; OR, 0.05; 95% CI, 0.002-0.98). Omalizumab improved IFN-α responses to rhinovirus, and within the omalizumab group, greater IFN-α increases were associated with fewer exacerbations (OR, 0.14; 95% CI, 0.01-0.88). Adverse events were rare and similar among arms. Conclusions Adding omalizumab before return to school to ongoing guidelines-based care among inner-city youth reduces fall asthma exacerbations, particularly among those with a recent exacerbation.
Background Epigenetic marks are heritable, influenced by the environment, direct the maturation of T lymphocytes, and in mice enhance the development of allergic airway disease. Thus it is important ...to define epigenetic alterations in asthmatic populations. Objective We hypothesize that epigenetic alterations in circulating PBMCs are associated with allergic asthma. Methods We compared DNA methylation patterns and gene expression in inner-city children with persistent atopic asthma versus healthy control subjects by using DNA and RNA from PBMCs. Results were validated in an independent population of asthmatic patients. Results Comparing asthmatic patients (n = 97) with control subjects (n = 97), we identified 81 regions that were differentially methylated. Several immune genes were hypomethylated in asthma, including IL13 , RUNX3 , and specific genes relevant to T lymphocytes ( TIGIT ). Among asthmatic patients, 11 differentially methylated regions were associated with higher serum IgE concentrations, and 16 were associated with percent predicted FEV1 . Hypomethylated and hypermethylated regions were associated with increased and decreased gene expression, respectively ( P < 6 × 10−12 for asthma and P < .01 for IgE). We further explored the relationship between DNA methylation and gene expression using an integrative analysis and identified additional candidates relevant to asthma ( IL4 and ST2 ). Methylation marks involved in T-cell maturation (RUNX3) , TH 2 immunity (IL4) , and oxidative stress (catalase) were validated in an independent asthmatic cohort of children living in the inner city. Conclusions Our results demonstrate that DNA methylation marks in specific gene loci are associated with asthma and suggest that epigenetic changes might play a role in establishing the immune phenotype associated with asthma.
Background IgE cross-linking triggers many cellular processes that drive allergic disease. While the role of IgE in mediating allergic responses is best described on basophils and mast cells, ...expression of the high-affinity IgE receptor on other innate immune cells, including monocytes, suggests that it may affect the function of these cells in allergic environments. Objective To determine the effect of IgE cross-linking on the function of human monocytes. Methods Monocytes purified from healthy donor blood samples were cultured for 4 to 96 hours with media alone, a cross-linking anti-IgE antibody or control IgG. Surface CD14 and CD64 expression and secreted cytokine concentrations were determined. Monocyte function was determined by assessing (1) phagocytosis of Escherichia coli or apoptotic HEp2 cells and (2) killing of intracellular E coli . Select experiments were performed on monocytes obtained from participants with elevated versus normal serum IgE concentrations. Results IgE cross-linking on monocytes increased CD14 expression and induced secretion of TNF-α, IL-6, and autoregulatory IL-10. These effects were greatest in individuals with elevated serum IgE concentrations. In contrast, IgE cross-linking reduced CD64 expression and significantly impaired phagocytic function without disrupting the capacity of monocytes to kill bacteria. Conclusions IgE cross-linking drives monocyte proinflammatory processes and autoregulatory IL-10 in a serum IgE-dependent manner. In contrast, monocyte phagocytic function is critically impaired by IgE cross-linking. Our findings suggest that IgE cross-linking on monocytes may contribute to allergic disease by both enhancing detrimental inflammatory responses and concomitantly crippling phagocytosis, a primary mechanism used by these cells to resolve inflammation.
The role of dendritic cells in asthma Gill, Michelle Ann, MD, PhD
Journal of allergy and clinical immunology,
04/2012, Letnik:
129, Številka:
4
Journal Article
Recenzirano
Dendritic cells (DCs) are known to play a central role in sensing the presence of foreign antigens and infectious agents and in initiating appropriate immune responses. More recently, an additional ...role has been discovered for DCs in determining whether the response to potential environmental allergens will be one of tolerance or whether a vigorous response along allergic pathways will be initiated. This review discusses ways in which DCs participate specifically in initiating allergic responses, particularly those associated with allergic asthma, and how interventions focused on DCs might lead to new therapeutic approaches to asthma.
...treatment regimens that specifically target inflammatory pathways characteristic of asthma severity in African Americans may be beneficial in treating this at risk population.
PBMC expression of glucocorticoid receptor alpha (GRalpha), corticosteroid transactivation (FK binding protein 5 (FKBP5)) and transrepression markers (IL-8, TNFalpha) at baseline and in response to ...10-8M fluticasone were determined by RT-PCR.
Background Children with allergic asthma have more frequent and severe human rhinovirus (HRV)–induced wheezing and asthma exacerbations through unclear mechanisms. Objective We sought to determine ...whether increased high-affinity IgE receptor (FcϵRI) expression and cross-linking impairs innate immune responses to HRV, particularly in allergic asthmatic children. Methods PBMCs were obtained from 44 children, and surface expression of FcϵRI on plasmacytoid dendritic cells (pDCs), myeloid dendritic cells, monocytes, and basophils was assessed by using flow cytometry. Cells were also incubated with rabbit anti-human IgE to cross-link FcϵRI, followed by stimulation with HRV-16, and IFN-α and IFN-λ1 production was measured by Luminex. The relationships among FcϵRI expression and cross-linking, HRV-induced IFN-α and IFN-λ1 production, and childhood allergy and asthma were subsequently analyzed. Results FcϵRIα expression on pDCs was inversely associated with HRV-induced IFN-α and IFN-λ1 production. Cross-linking FcϵRI before HRV stimulation further reduced PBMC IFN-α (47% relative reduction; 95% CI, 32% to 62%; P < .0001) and IFN-λ1 (81% relative reduction; 95% CI, 69% to 93%; P < .0001) secretion. Allergic asthmatic children had higher surface expression of FcϵRIα on pDCs and myeloid dendritic cells when compared with that seen in nonallergic nonasthmatic children. Furthermore, after FcϵRI cross-linking, allergic asthmatic children had significantly lower HRV-induced IFN responses than allergic nonasthmatic children (IFN-α, P = .004; IFN-λ1, P = .02) and nonallergic nonasthmatic children (IFN-α, P = .002; IFN-λ1, P = .01). Conclusions Allergic asthmatic children have impaired innate immune responses to HRV that correlate with increased FcϵRI expression on pDCs and are reduced by FcϵRI cross-linking. These effects likely increase susceptibility to HRV-induced wheezing and asthma exacerbations.
DNA Methylation and Childhood Asthma in the Inner-City Yang, Ivana, PhD; Liu, Andrew H., MD, FAAAAI; Pedersen, Brent, PhD ...
Journal of allergy and clinical immunology,
02/2015, Letnik:
135, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Methods We compared DNA methylation patterns and gene expression in African American inner city children with persistent atopic asthma versus healthy controls, using DNA and RNA from peripheral blood ...mononuclear cells (PBMCs).
Treatment regimens for omalizumab are guided by a dosing table that is based on total serum IgE and body weight. Limited data exist about onset and offset of omalizumab efficacy in children and ...adolescents or subgroups that most benefit from treatment.
Post hoc analyses were conducted to (1) examine patient characteristics of those eligible and ineligible for omalizumab, (2) describe onset of effect after initiation of omalizumab and offset of treatment effect after stopping therapy, and (3) determine whether the efficacy differs by age, asthma severity, dosing regimen, and prespecified biomarkers.
Inner-city children and adolescents with persistent allergic asthma were enrolled in the Inner-City Anti-IgE Therapy for Asthma trial that compared omalizumab with placebo added to guidelines-based therapy for 60 weeks.
Two hundred ninety-three of 889 participants (33%) clinically suitable for omalizumab were ineligible for dosing according to a modified dosing table specifying IgE level and body weight criteria. Baseline symptoms were comparable among those eligible and ineligible to receive omalizumab, but other characteristics (rate of health care utilization and skin test results) differed. The time of onset of omalizumab effect was <30 days and time of offset was between 30 and 120 days. No difference in efficacy was noted by age or asthma severity, but high exhaled nitric oxide, blood eosinophils, and body mass index predicted efficacy.
A significant portion of children and adolescents particularly suited for omalizumab because of asthma severity status may be ineligible due to IgE >1300 IU/mL. Omalizumab reduced asthma symptoms and exacerbations rapidly; features associated with efficacy can be identified to guide patient selection.
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