Preferential role for NF-kappa B/Rel signaling in the type 1 but not type 2 T cell-dependent immune response in vivo.
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T cell function is a critical determinant of immune responses as well as susceptibility to allergic diseases. Activated T cells can differentiate into effectors whose cytokine profile is limited to type 1 (IFN-gamma-dominant) or type 2 (IL-4-, IL-5-dominant) patterns. To investigate mechanisms that connect extracellular stimuli with the regulation of effector T cell function, we have measured immune responses of transgenic mice whose NF-kappa B/Rel signaling pathway is inhibited in T cells. Surprisingly, these mice developed type 2 T cell-dependent responses (IgE and eosinophil recruitment) in a model of allergic pulmonary inflammation. In contrast, type 1 T cell responses were severely impaired, as evidenced by markedly diminished delayed-type hypersensitivity responses, IFN-gamma production, and Ag-specific IgG2a levels. Taken together, these data indicate that inhibition of NF-kappa B can lead to preferential impairment of type 1 as compared with type 2 T cell-dependent responses. (+info)
Inhibitory effects of endogenous and exogenous interferon-gamma on bronchial hyperresponsiveness, allergic inflammation and T-helper 2 cytokines in Brown-Norway rats.
(58/1734)
Interferon-gamma (IFN-gamma) is an important cytokine involved in the regulation of allergen-induced immune responses. We examined the role of IFN-gamma in a Brown-Norway rat model of bronchial hyperresponsiveness (BHR) and airway eosinophilia, and its effects on the mRNA expression of T helper type 1 (Th1)/Th2 cytokine. Ovalbumin (OA)-sensitized animals were given either exogenous IFN-gamma (105 U/rat over 3 days, intraperitoneally) or anti-IFN-gamma blocking antibody (DB-1 0.3 mg/rat, intravenously) prior to exposure to OA aerosol and were studied 18-24 hr later. In sensitized animals, OA induced significant BHR, accumulation of eosinophils, T lymphocytes and neutrophils in bronchoalveolar lavage (BAL) fluid, and also increased eosinophils and CD8+ T cells in the airways. Exogenous IFN-gamma attenuated allergen-induced BHR (P<0.02, compared with sham-treated animals) together with a significant reduction in eosinophil and neutrophil numbers in BAL fluid (P<0. 005), and eosinophils and CD8+ T cells in airways (P<0.05). By contrast, anti-IFN-gamma antibody increased airway CD4+ T cells and BHR. Using reverse transcriptase-polymerase chain reaction, significant increases in Th2 [interleukin-4 (IL-4), IL-5 and IL-10], and IFN-gamma cytokine mRNA were found in the lungs of sensitized and OA-exposed animals, while exogenous IFN-gamma significantly suppressed IL-4, IL-5 and IL-10 mRNA expression, and anti-IFN-gamma antibody increased IL-4 and IL-5 mRNA expression. These results indicate that Th1 effects, such as those mediated by IFN-gamma, play a down-regulatory role to suppress the Th2 responses associated with allergen-induced BHR and eosinophilic inflammation. (+info)
Transgenic overexpression of beta(2)-adrenergic receptors in airway smooth muscle alters myocyte function and ablates bronchial hyperreactivity.
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beta(2)-Adrenergic receptors (beta(2)AR) act to relax airway smooth muscle and can serve to counteract hyperresponsiveness, although the effect may not be ablative even in the presence of exogenous agonist. Within this signaling cascade that ultimately transduces smooth muscle relaxation, a significant "spare receptor" pool has been hypothesized to be present in the airway. In order to modify the relationship between beta(2)AR and downstream effectors, transgenic mice (TG) were created overexpressing beta(2)AR approximately 75-fold in airway smooth muscle using a mouse smooth muscle alpha-actin promoter. While >90% of these receptors were expressed on the smooth muscle cell surface, the percentage of receptors able to form the agonist-promoted high affinity complex was less than that found with nontransgenic (NTG) cells (R(H) = 18 versus 36%). Nevertheless, beta(2)AR signaling was found to be enhanced. Intact airway smooth muscle cells from TG had basal cAMP levels that were greater than NTG cells. A marked increase in agonist-stimulated cAMP levels was found in the TG ( approximately 200% stimulation over basal) compared with NTG ( approximately 50% over basal) cells. Adenylyl cyclase studies gave similar results and also showed a 10-fold lower EC(50) for TG cells. Tracheal rings from TG mice that were precontracted with acetylcholine had an enhanced responsiveness (relaxation) to beta-agonist, with a 60-fold decrease in the ED(50), indicating that the enhanced signaling imposed by overexpression results in an increase in the coordinated function of the intact airway cells. In vivo studies showed a significantly blunted airway resistance response to the inhaled bronchoconstrictor methacholine in the TG mice. Indeed, with beta-agonist pretreatment, the TG mice displayed no response whatsoever to methacholine. These results are consistent with beta(2)AR being the limiting factor in the transduction system. Increases in the initial component of this transduction system (the beta(2)AR) are sufficient to markedly alter signaling and airway smooth muscle function to the extent that bronchial hyperresponsiveness is ablated, consistent with an anti-asthma phenotype. (+info)
Repeated allergen exposure of sensitized Brown-Norway rats induces airway cell DNA synthesis and remodelling.
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Chronic inflammation in asthmatic airways can lead to characteristic airway smooth muscle (ASM) thickening and pathological changes within the airway wall. This study assessed the effect of repeated allergen exposure on ASM and epithelial cell deoxyribonucleic acid (DNA) synthesis, cell recruitment and airway wall pathology. Brown-Norway rats were sensitized and then exposed to ovalbumin or saline aerosol every 3 days on six occasions. After the final exposure, rats were administered twice daily for 7 days with the DNA S-phase marker bromodeoxyuridine (BrdU). Using a triple immunohistochemical staining technique, BrdU incorporation into ASM and epithelium was quantified employing computer-assisted image analysis. There were >3-fold mean increases in BrdU incorporation into ASM from 1.3% of cells (95% confidence interval (CI) 1.0-1.6) in saline controls to 4.7% (95% CI 2.6-6.7) after allergen exposure (p<0.001), and in airway epithelium, from 1.3 (95% CI 0.6-2.0) BrdU-positive cells x mm basement membrane(-1) in saline controls to 4.9 (95% CI 3.0-6.7) after allergen exposure (p<0.001). There was increased subepithelial collagen deposition and mucus secretion along with a significant eosinophil and lymphocyte recruitment to the airways. Increased rates of deoxyribonucleic acid synthesis in both airway smooth muscle and epithelial cells along with changes to the airway wall pathology may precede the establishment of smooth muscle thickening and airway remodelling after repeated allergen exposure in rats. This model seems to be appropriate for studying structural changes within the airways as observed in asthma. (+info)
Asthma survey items as predictors of respiratory problems in children 2 yrs later: a longitudinal study.
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The study compared the ability of characteristics defined by an asthma survey (wheeze versus cough and asthma diagnosis versus no diagnosis) to predict later respiratory problems in a cohort of 108 schoolchildren who had reported either recent wheeze or recurrent cough in a 1987 asthma survey. The children recorded daily respiratory symptoms and peak flow from April 1989 until May 1990. The frequency and severity of lower respiratory symptom episodes and peak flow dips were compared in the wheeze and cough groups and in the diagnosed versus nondiagnosed children. The independent effects of initial wheeze, atopy, diagnosis and bronchial hyperresponsiveness (BHR) on the longitudinal outcome measures were assessed using multiple linear regression. Children with initial wheeze had more chronic symptoms and peak flow variability than those with cough alone, but wheeze had only a weak effect on frequency and severity of acute lower respiratory episodes. Children with both wheeze and atopy had more acute symptomatic episodes and more chronic symptoms than did the other children. Children with diagnosed asthma (versus no diagnosis) had significantly more frequent and severe lower respiratory exacerbations, more days symptomatic and greater peak flow variability. The predictive effects of diagnosis were independent of (and stronger than the effects of) wheeze, atopy and BHR, or combinations of these variables. The results suggest that among children who report respiratory symptoms, survey-reported wheeze on its own is a weaker marker of significant respiratory disease than is a doctor's diagnosis of asthma. (+info)
Cut-off points defining normal and asthmatic bronchial reactivity to exercise and inhalation challenges in children and young adults.
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An analysis was undertaken to determine the optimal cut-off separating an asthmatic from a normal response to a bronchial provocation challenge by exercise and the inhalation of methacholine or histamine in children and young adults. Data were extracted, after appropriate correction, from published studies available in Medline of large random populations that complied with preset criteria of suitability for analysis, and the distribution of bronchial reactivity in the healthy population for exercise and inhalation challenges were derived. Studies on the response to exercise and methacholine inhalation in 232 young asthmatics of varying severity were carried out by the authors and the distribution of bronchial reactivity of a young asthmatic population obtained. Comparisons of the sensitivity and specificity of the challenges were aided by the construction of receiver operating characteristic curves. The optimal cut-off point of the fall in forced expiratory volume in one second (FEV1) after exercise was 13%, with a sensitivity (power) of 63% and specificity of 94%. For inhalation challenges, the optimal cut-off point for the dose of methacholine or histamine causing a 20% fall in FEV1 was 6.6 micromol, with a sensitivity of 92% and a specificity of 89%. The cut-off values were not materially affected by the severity of the asthma and provide objective data with which to evaluate the results of bronchial provocation challenges in children and young adults. (+info)
Inner city air pollution and respiratory health and atopy in children.
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The impact of inner city air pollution on the development of respiratory and atopic diseases in childhood is still unclear. In a cross sectional study in Dresden, Germany, 5,421 children in two age groups (5-7 yrs and 9-11 yrs) were studied according to the International Study of Asthma and Allergies in Childhood (ISAAC) phase II protocol. The prevalences of wheezing and cough as well as doctor diagnosed asthma and bronchitis were assessed by parental questionnaires. Children also underwent skin-prick testing, venipuncture for the measurement of serum immunoglobulin (Ig)E, lung function testing and a bronchial challenge test (4.5% saline) to assess airway hyperresponsiveness. Exposure was assessed on an individual basis by relating mean annual air pollution levels (SO2, NO2, CO, benzene, and O3) which had been measured on a 1 km2 grid, to the home and school address of each study subject. After adjusting for potential confounding factors an increase in the exposure to benzene of 1 microg x m3 air was associated with an increased prevalence of morning cough (adjusted odds ratio (aOR)): 1.15; 1.04-1.27) and bronchitis (aOR: 1.11; 1.03-1.19). Similar associations were observed for NO2 and CO. In turn, the prevalences of atopic sensitization, symptoms of atopic diseases and bronchial hyperresponsiveness were not positively associated with exposure to any of these pollutants. It is concluded that in this study a moderate increase in exposure to traffic-related air pollution was associated with an increased prevalence of cough and bronchitis, but not with atopic conditions in children. (+info)
Transfer of the enhancing effect of respiratory syncytial virus infection on subsequent allergic airway sensitization by T lymphocytes.
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In mice, respiratory syncytial virus (RSV) infection enhances allergic airway sensitization, resulting in lung eosinophilia and in airway hyperresponsiveness (AHR). The mechanisms by which RSV contributes to development of asthma and its effects on allergic airway sensitization in mice are not known. We tested whether these consequences of RSV infection can be adoptively transferred by T cells and whether depletion of T cell subsets prevents the effects of RSV infection on subsequent airway sensitization. Mononuclear cells, T lymphocytes, or CD4 or CD8 T cells from peribronchial lymph nodes (PBLN) of RSV-infected mice were transferred into naive BALB/c mice which were then exposed to OVA via the airways. Additionally, RSV-infected mice were depleted of CD4 or CD8 T cells following acute RSV infection but prior to airway sensitization. Following sensitization, airway responsiveness to inhaled methacholine, numbers of lung eosinophils, and levels of IFN-gamma, IL-4, and IL-5 in PBLN cell cultures were monitored. Transfer of T cells from RSV-infected mice resulted in increased eosinophil influx into the lungs, increased IL-5 production, and development of AHR following airway sensitization to allergen. Transfer of CD8 but not CD4 T cells from the PBLN of RSV-infected mice also resulted in AHR following 10 days of OVA exposure. Further, depletion of CD8 T cells prevented these consequences of RSV infection while CD4 T cell depletion reduced them. We conclude that T cells, in particular CD8 T cells, are critical in mediating RSV-induced development of lung eosinophilia and AHR following allergic airway sensitization. (+info)