RESUMEN
Pulmonary fibrosis is a progressive inflammatory disease with high mortality and limited therapeutic options. Previous genetic and immunologic investigations suggest common intersections between idiopathic pulmonary fibrosis (IPF), sarcoidosis, and murine models of pulmonary fibrosis. To identify immune responses that precede collagen deposition, we conducted molecular, immunohistochemical, and flow cytometric analysis of human and murine specimens. Immunohistochemistry revealed programmed cell death-1 (PD-1) up-regulation on IPF lymphocytes. PD-1+CD4+ T cells with reduced proliferative capacity and increased transforming growth factor-ß (TGF-ß)/interleukin-17A (IL-17A) expression were detected in IPF, sarcoidosis, and bleomycin CD4+ T cells. PD-1+ T helper 17 cells are the predominant CD4+ T cell subset expressing TGF-ß. Coculture of PD-1+CD4+ T cells with human lung fibroblasts induced collagen-1 production. Strikingly, ex vivo PD-1 pathway blockade resulted in reductions in TGF-ß and IL-17A expression from CD4+ T cells, with concomitant declines in collagen-1 production from fibroblasts. Molecular analysis demonstrated PD-1 regulation of the transcription factor STAT3 (signal transducer and activator of transcription 3). Chemical blockade of STAT3, using the inhibitor STATTIC, inhibited collagen-1 production. Both bleomycin administration to PD-1 null mice or use of antibody against programmed cell death ligand 1 (PD-L1) demonstrated significantly reduced fibrosis compared to controls. This work identifies a critical, previously unrecognized role for PD-1+CD4+ T cells in pulmonary fibrosis, supporting the use of readily available therapeutics that directly address interstitial lung disease pathophysiology.
Asunto(s)
Linfocitos T CD4-Positivos/metabolismo , Fibrosis Pulmonar Idiopática/inmunología , Fibrosis Pulmonar Idiopática/patología , Interleucina-17/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , Factor de Transcripción STAT3/metabolismo , Factor de Crecimiento Transformador beta1/biosíntesis , Regulación hacia Arriba , Adulto , Anciano , Animales , Bleomicina , Proliferación Celular , Colágeno Tipo I/metabolismo , Modelos Animales de Enfermedad , Femenino , Fibroblastos/metabolismo , Regulación de la Expresión Génica , Humanos , Fibrosis Pulmonar Idiopática/genética , Masculino , Ratones , Persona de Mediana Edad , ARN Mensajero/genética , ARN Mensajero/metabolismo , Factor de Transcripción STAT3/genética , Sarcoidosis/inmunología , Sarcoidosis/patología , Células Th17/metabolismoRESUMEN
The mechanisms by which chronic inflammatory lung diseases, particularly chronic obstructive pulmonary disease, confer enhanced risk for lung cancer are not well-defined. To investigate whether nuclear factor (NF)-κB, a key mediator of immune and inflammatory responses, provides an interface between persistent lung inflammation and carcinogenesis, we utilized tetracycline-inducible transgenic mice expressing constitutively active IκB kinase ß in airway epithelium (IKTA (IKKß trans-activated) mice). Intraperitoneal injection of ethyl carbamate (urethane), or 3-methylcholanthrene (MCA) and butylated hydroxytoluene (BHT) was used to induce lung tumorigenesis. Doxycycline-treated IKTA mice developed chronic airway inflammation and markedly increased numbers of lung tumors in response to urethane, even when transgene expression (and therefore epithelial NF-κB activation) was begun after exposure to carcinogen. Studies using a separate tumor initiator/promoter model (MCA+BHT) indicated that NF-κB functions as an independent tumor promoter. Enhanced tumor formation in IKTA mice was preceded by increased proliferation and reduced apoptosis of alveolar epithelium, resulting in increased formation of premalignant lesions. Investigation of inflammatory cells in lungs of IKTA mice revealed a substantial increase in macrophages and lymphocytes, including functional CD4+/CD25+/FoxP3+ regulatory T lymphocytes (Tregs). Importantly, Treg depletion using repetitive injections of anti-CD25 antibodies limited excessive tumor formation in IKTA mice. At 6 weeks following urethane injection, antibody-mediated Treg depletion in IKTA mice reduced the number of premalignant lesions in the lungs in association with an increase in CD8 lymphocytes. Thus, persistent NF-κB signaling in airway epithelium facilitates carcinogenesis by sculpting the immune/inflammatory environment in the lungs.
Asunto(s)
Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , FN-kappa B/metabolismo , Transducción de Señal , Linfocitos T Reguladores/inmunología , Animales , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Enfermedad Crónica , Epitelio/efectos de los fármacos , Epitelio/inmunología , Epitelio/metabolismo , Epitelio/patología , Humanos , Inflamación/inmunología , Inflamación/metabolismo , Inflamación/patología , Pulmón/efectos de los fármacos , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/patología , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/metabolismo , Ratones , Comunicación Paracrina/efectos de los fármacos , Linfocitos T Reguladores/efectos de los fármacos , Factores de Tiempo , Uretano/efectos adversosRESUMEN
A relationship between infections and allergic airway disease has long been recognized, and many reviews have been written on this topic. However, both clinical and basic science studies published in the last 3 years provide new insights into the relationship between infection and allergic conditions. In this review, we focus on these very recent studies, which address the role of infection in the development, maintenance, and exacerbation of asthma. Bacterial, viral, fungal, and parasitic infections have each been examined and provide a framework for these novel concepts.
Asunto(s)
Asma/microbiología , Infecciones/complicaciones , Asma/inmunología , Humanos , Hipersensibilidad/inmunología , Hipersensibilidad/microbiología , Infecciones/inmunologíaRESUMEN
Cyclooxygenase-2 (COX-2) gene expression in the lung is induced in pathological conditions such as asthma and pneumonia; however, the exact impact of COX-2 gene expression in the airway in regulating inflammatory and immunological response in the lung is not understood. To define a physiological role of inducible COX-2 in airway epithelial cells, we developed a novel line of transgenic mice, referred to as CycloOxygenase-2 TransActivated (COTA) mice, that overexpress a COX-2 transgene in the distribution of the CC-10 promoter in response to doxycycline. In response to doxycycline treatment, COX-2 expression was increased in airway epithelium of COTA mice and whole lung tissue contained a three- to sevenfold increase in prostaglandin E(2) (PGE(2)), prostaglandin D(2) (PGD(2)) thromboxane B(2) (TXB(2)) and 6-Keto prostaglandin F(2alpha) (PGF(2alpha)) compared to wild-type and untreated COTA mice. Interestingly, primary mouse tracheal epithelial cells from COTA mice produced only PGE(2) by doxycycline-induced COX-2 activation, providing an indication of cellular specificity in terms of mediator production. In the ovalbumin model, in which doxycycline was given at the sensitization stage, there was an increase in interleukin (IL)-4 level in lung tissue from COTA mice compared to untreated COTA and wild-type mice. In addition, COTA mice that were treated with doxycycline had impaired clearance of Pseudomonas aeruginosa pneumonia compared to wild-type mice. COX-2 gene expression in airway epithelial cells has an important role in determining immunological response to infectious and allergic agents.
Asunto(s)
Bronquios/enzimología , Ciclooxigenasa 2/inmunología , Regulación Enzimológica de la Expresión Génica/inmunología , Mucosa Respiratoria/inmunología , Tráquea/enzimología , Animales , Bronquios/inmunología , Células Cultivadas , Ciclooxigenasa 2/genética , Dinoprostona/biosíntesis , Células Epiteliales/enzimología , Células Epiteliales/inmunología , Genotipo , Inmunidad Mucosa , Interleucina-4/biosíntesis , Ratones , Ratones Transgénicos , Prostaglandinas/biosíntesis , Infecciones por Pseudomonas/inmunología , Infecciones por Pseudomonas/microbiología , Pseudomonas aeruginosa/crecimiento & desarrollo , Tráquea/inmunologíaRESUMEN
BACKGROUND: Smooth muscle contraction is one of the hallmarks of asthma. A recently developed pyridine derivative, Y-27632, a selective Rho kinase inhibitor, has been reported to inhibit the smooth muscle contraction of human and animal trachea in ex vivo systems but its effect in animal models of airway hyperresponsiveness (AHR) has not been examined. The purpose of this study was to evaluate the effect of Y-27632 in a murine model of allergic and virally induced AHR. METHODS: Baseline lung resistance and methacholine induced AHR were measured in mice sensitised to ovalbumin (OVA) and also in mice infected with respiratory syncytial virus (RSV) following ovalbumin sensitisation (OVA/RSV). RESULTS: Time course and dose ranging experiments indicated that 30 mg/kg Y-27632 given by gavage 2 hours before methacholine challenge significantly reduced baseline lung resistance and prevented AHR in OVA sensitised mice. Y-27632 also suppressed AHR induced by the bronchospastic agent serotonin in OVA sensitised mice and prevented methacholine induced AHR in OVA/RSV mice. CONCLUSIONS: These results suggest that the signalling pathway mediated through Rho kinase may have an important role in bronchial smooth muscle tone in allergen induced and virus induced AHR and should be considered as a novel target for asthma treatment.
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Antihipertensivos/uso terapéutico , Benzopiranos/uso terapéutico , Hiperreactividad Bronquial/tratamiento farmacológico , Infecciones por Virus Sincitial Respiratorio/complicaciones , Resistencia de las Vías Respiratorias/efectos de los fármacos , Animales , Asma/tratamiento farmacológico , Asma/fisiopatología , Hiperreactividad Bronquial/etiología , Relación Dosis-Respuesta a Droga , Femenino , Pulmón/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , OvalbúminaRESUMEN
Severe respiratory syncytial virus (RSV) infection has been hypothesized to be a risk factor for the development of allergy and asthma, but epidemiologic studies in humans have been inconclusive. By use of a well-characterized murine model of RSV infection and allergic sensitization with ovalbumin, the effect of a preceding severe RSV infection on the development of the pulmonary allergic inflammatory response and airway hyperresponsiveness (AHR) was tested. The impact of prior allergic sensitization on RSV-induced illness, as measured by weight loss, also was evaluated. RSV infection before allergic sensitization decreased allergen-induced AHR, production of interleukin-13 in lung tissue, and lung eosinophilia. In contrast, allergic sensitization before RSV infection increased AHR and decreased RSV-related weight loss and lung levels of interferon-gamma but did not alter viral clearance. These data provide evidence that RSV-associated AHR occurs in hosts with allergic responses and that allergic inflammation is diminished when preceded by RSV infection.
Asunto(s)
Hipersensibilidad/inmunología , Ovalbúmina/inmunología , Infecciones por Virus Sincitial Respiratorio/complicaciones , Alérgenos/inmunología , Animales , Hiperreactividad Bronquial/diagnóstico , Hiperreactividad Bronquial/virología , Broncoconstrictores , Femenino , Hipersensibilidad/complicaciones , Interferón gamma/biosíntesis , Interleucina-13/biosíntesis , Pulmón/inmunología , Pulmón/virología , Recuento de Linfocitos , Cloruro de Metacolina , Ratones , Ratones Endogámicos BALB C , Eosinofilia Pulmonar/complicaciones , Eosinofilia Pulmonar/inmunología , Infecciones por Virus Sincitial Respiratorio/inmunología , Infecciones por Virus Sincitial Respiratorio/virología , Virus Sincitiales Respiratorios/crecimiento & desarrollo , Factores de Tiempo , Replicación Viral , Pérdida de PesoRESUMEN
The interaction between viruses and dendritic cells (DCs) is varied and complex. DCs are key elements in the development of a host response to pathogens such as viruses, but viruses have developed survival tactics to either evade or diminish the immune system that functions to kill and eliminate these micro-organisms. In the present review we summarize current concepts regarding the function of DCs in the immune system, our understanding of how viruses alter DC function to attenuate both the virus-specific and global immune response, and how we may be able to exploit DC function to prevent or treat viral infections.
Asunto(s)
Células Dendríticas/fisiología , Pulmón/inmunología , Virosis/inmunología , Animales , Células Presentadoras de Antígenos/fisiología , HumanosRESUMEN
BACKGROUND: The mechanisms behind airway hyperresponsiveness in asthma are unknown. Airway wall edema has been proposed as one possible culprit of this phenomenon. OBJECTIVE: To test the hypothesis that airway edema may be the cause of allergen-induced increases in airway responsiveness in asthma, this trial aimed at determining the relationship between allergen-induced changes in airway responsiveness to inhaled methacholine and indirect indices of edema, namely peripheral airway resistance and the levels of the plasma protein fibrinogen in bronchoalveolar lavage (BAL) fluids. METHODS: Twenty-six atopic individuals with mild asthma were subjected to bronchoscopy at baseline and 28 hours after allergen inhalation. Before each bronchoscopy, methacholine bronchoprovocation was performed. During bronchoscopy, peripheral airway resistance measurements were obtained by wedged bronchoscopy. BAL fluids were analyzed for fibrinogen, as well as for eosinophilic cationic protein. Cytology was performed, and cytokine gene expression was assessed with competitive reverse transcriptase PCR from cell pellets. RESULTS: A significant increase in airway responsiveness to methacholine was recorded after allergen, but this did not correlate with changes in peripheral airway resistance (which was not affected) or with BAL fibrinogen (which decreased after allergen). Other BAL outcomes confirmed that airway inflammation was produced and was characterized by a T(H)2 cytokine pattern. CONCLUSIONS: Airway responsiveness in asthma increases after exposure to allergen in the absence of increased indirect indices of edema. The role of edema in this phenomenon should therefore be tested more vigorously.
Asunto(s)
Alérgenos/efectos adversos , Hiperreactividad Bronquial/inducido químicamente , Edema/inducido químicamente , Enfermedades Respiratorias/inducido químicamente , Ribonucleasas , Resistencia de las Vías Respiratorias/efectos de los fármacos , Alérgenos/farmacología , Asma/inmunología , Asma/fisiopatología , Proteínas Sanguíneas/análisis , Pruebas de Provocación Bronquial , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/citología , Broncoscopía , Citocinas/biosíntesis , Citocinas/genética , Citocinas/metabolismo , Proteínas en los Gránulos del Eosinófilo , Fibrinógeno/análisis , Perfilación de la Expresión Génica , Humanos , Hipersensibilidad Inmediata/inmunología , Hipersensibilidad Inmediata/fisiopatología , Interferón gamma/biosíntesis , Interferón gamma/genética , Interleucina-2/biosíntesis , Interleucina-2/genética , Interleucina-4/biosíntesis , Interleucina-4/genética , Interleucina-5/biosíntesis , Interleucina-5/genética , Cloruro de Metacolina , ARN Mensajero/biosíntesis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células Th2/inmunología , Células Th2/metabolismoRESUMEN
The mechanism(s) leading to the development of late phase allergic reactions is (are) unknown. Previous studies have indicated that a relationship between serum IgE and the late phase exists. To explore the relationships between allergen-specific immunoglobulins in bronchoalveolar lavage (BAL) fluids and the magnitude of airflow limitation during the late phase response to inhaled allergen. Ragweed-specific IgE, IgA, secretory IgA (sIgA) and IgG were measured in BAL fluid and in the serum 1-5 weeks before whole lung antigen challenge with ragweed extract, in 16 ragweed allergic asthmatics. In addition, BAL and serum eosinophil cationic protein (ECP) and BAL fibrinogen levels were determined and BAL cells counted and differentiated. The latter procedures were repeated in a second BAL performed 24 h after the end of the ragweed challenge. After the challenge, lung function was monitored hourly for 8 h, to record the magnitude of airflow limitation. Ragweed-specific immunoglobulins were detected in 25% to 37.5% of BAL samples. Compared to the subjects with undetectable BAL fluid ragweed-specific IgE levels at baseline, those with detectable antibodies had stronger late phase reactions as determined by the nadir of FEV1 between hours 4 and 8 after the ragweed inhalation challenge (P = 0.0007). Allergen-induced changes in BAL ECP and fibrinogen levels were also higher in those subjects with detectable ragweed-specific IgE in baseline fluids (P = 0.03 and P = 0.005, respectively). Significant relationships between BAL antigen-specific IgA, serum ragweed-specific IgE and IgA and the late phase reaction were also found. The results of this study point towards the possibility that allergen-specific IgE and IgA may be independently involved in the pathogenesis of the late phase reaction. This notion merits further exploration.
Asunto(s)
Asma/inmunología , Líquido del Lavado Bronquioalveolar/inmunología , Inmunoglobulina A/biosíntesis , Inmunoglobulina E/biosíntesis , Polen/inmunología , Ribonucleasas , Adulto , Alérgenos/inmunología , Antígenos/inmunología , Proteínas Sanguíneas/biosíntesis , Proteínas en los Gránulos del Eosinófilo , Eosinófilos/inmunología , Femenino , Fibrinógeno/biosíntesis , Volumen Espiratorio Forzado , Humanos , Recuento de Leucocitos , Masculino , Extractos Vegetales/inmunologíaRESUMEN
Severe respiratory syncytial virus (RSV)-induced disease is associated with childhood asthma and atopy. We combined murine models of allergen-sensitization and RSV infection to explore the interaction of allergic and virus-induced airway inflammation and its impact on airway hyperresponsiveness (AHR). We found that RSV infection during ova-sensitization (OVA/RSV) increased and prolonged AHR compared to mice only RSV-infected (RSV) or ova-sensitized (OVA). AHR is known to be associated with an increase in Type 2 cytokines (IL-4, IL-5, and IL-13) in allergen-sensitized mice. Therefore, we hypothesized that RSV-induced enhancement of AHR was a result of potentiating the Type 2 cytokine profile promoted by ova-sensitization. Surprisingly, we found that Type 2 cytokines induced by ova-sensitization were not increased by RSV infection despite the increase in AHR, and in some cases were diminished. RNAse protection assay revealed no difference in IL-4 and IL-5 mRNA levels between the OVA and OVA/RSV groups, and IL-13 mRNA was significantly decreased in the OVA/RSV mice compared to the OVA group. Flow cytometric analysis of Type 2 cytokines demonstrated the same frequency of IL-4 and IL-5 production in lung-derived T lymphocytes from the OVA/RSV and OVA groups. Direct cytokine ELISA measurements of lung supernatant showed the level of IL-13 was significantly decreased in the OVA/RSV group compared to OVA mice, while there was no difference in either IL-4 or IL-5 between these two groups. These data indicate that the enhanced and prolonged AHR caused by the interaction of allergic airway inflammation and virus-induced immune responses is a complex process that can not be explained simply by augmented production of Type 2 cytokines.
Asunto(s)
Alérgenos/inmunología , Hipersensibilidad/inmunología , Infecciones por Virus Sincitial Respiratorio/inmunología , Virus Sincitiales Respiratorios , Animales , Citocinas/análisis , Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Citometría de Flujo , Inmunización , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Interleucina-5/metabolismo , Pulmón/inmunología , Linfocitos/inmunología , Ratones , Ratones Endogámicos BALB C , Ovalbúmina/inmunología , ARN Mensajero/análisis , Organismos Libres de Patógenos EspecíficosRESUMEN
The triggers and causes of asthma have long been topics of investigation by epidemiologists. The current concept of asthma and atopy is that the onset of the disease and its clinical course are determined by gene environment interactions; that is, those individuals who develop asthma are both genetically susceptible and receive appropriate environmental stimuli. One potential environmental factor that may relate to disease etiology is diet. This article will review the published evidence for the effects of dietary antioxidants on asthma incidence and disease control.
Asunto(s)
Antioxidantes/administración & dosificación , Asma/prevención & control , Dieta , Vitaminas/administración & dosificación , Adulto , Asma/epidemiología , Estudios Transversales , Humanos , Incidencia , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: Several studies suggest that endogenous glucocorticoids can dampen the severity of experimental allergic reactions in animals. OBJECTIVE: To investigate the influence that endogenous glucocorticoids have on the course of IgE-mediated pulmonary early and late phase reactions. METHODS: Twenty-one allergic asthmatic and six healthy control subjects underwent inhaled antigen challenge with measurements of plasma cortisol and cortisone by gas chromatography-mass spectrometry. RESULTS: There were no differences between the asthmatic and control groups in the baseline levels of cortisol or cortisone. However, the asthmatic subjects had significantly higher cortisol levels (67.2 +/- 8.6 vs 35.1 +/- 4.5 ng/mL; P = 0.04) and had higher cortisol/cortisone ratios (4.8 +/- 0. 6 vs 3.0 +/- 0.2; P = 0.01) 8 h after challenge compared to the control subjects. Among the asthmatic subjects, those whose FEV1 recovered rapidly had higher baseline levels of cortisol and those who displayed a late phase reaction had lower levels of cortisol during the late phase period. CONCLUSION: The results suggest that endogenous glucocorticoids may play a significant role in the modulation of airway responses to antigen challenge, and that antigen challenge may induce cortisol production in allergic subjects.
Asunto(s)
Antígenos/inmunología , Asma/fisiopatología , Broncoconstricción , Cortisona/sangre , Hidrocortisona/sangre , Mecánica Respiratoria , Adulto , Asma/sangre , Asma/inmunología , Pruebas de Provocación Bronquial , Femenino , Volumen Espiratorio Forzado , Humanos , Masculino , Persona de Mediana EdadRESUMEN
The immunomodulatory role of arachidonic acid metabolites in allergic sensitization is undefined. Prostaglandin E(2) (PGE(2)), a product of arachidonic acid metabolism through the cyclooxygenase pathway, has been reported to favor Type 2-like cytokine secretion profiles in murine and human CD4(+) T cells by inhibiting the production of Type 1-associated cytokines. On the basis of these in vitro data, we hypothesized that indomethacin, a nonselective cyclooxygenase inhibitor, would diminish allergen-induced production of Type 2 cytokines in mice, and protect against airway hyperresponsiveness (AHR) to methacholine. We found that ovalbumin-sensitized mice that were treated with indomethacin (OVA-indomethacin mice) had significantly greater AHR (p < 0.05) and higher levels of IL-5 (176 +/- 52 versus 66 +/- 4 pg/ml) and IL-13 (1,226 +/- 279 versus 475 +/- 65 pg/ml) in lung supernatants than mice sensitized with ovalbumin alone (OVA mice), while levels of IL-4 and serum IgE were not different. Lung mRNA expression of the C-C chemokine MCP-1 was increased in OVA-indomethacin mice, while there was no difference between the two groups in lung mRNA expression of eotaxin, MIP-1alpha, MIP-1beta, or MIP-2. Histologic examination revealed greater pulmonary interstitial eosinophilia in OVA-indomethacin mice as well. Contrary to our expectations, we conclude that in the BALB/c mouse, cyclooxygenase inhibition during allergen sensitization increases AHR, production of IL-5 and IL-13, and interstitial eosinophilia.
Asunto(s)
Inhibidores de la Ciclooxigenasa/farmacología , Hipersensibilidad/fisiopatología , Indometacina/farmacología , Interleucina-13/biosíntesis , Interleucina-5/biosíntesis , Hipersensibilidad Respiratoria/metabolismo , Animales , Ácido Araquidónico/metabolismo , Quimiocinas CC/análisis , Femenino , Inmunoglobulina E/sangre , Interleucina-4/análisis , Interleucina-6/análisis , Pulmón/química , Pulmón/patología , Cloruro de Metacolina , Ratones , Ratones Endogámicos BALB C , Ovalbúmina/inmunología , Hipersensibilidad Respiratoria/prevención & control , Organismos Libres de Patógenos EspecíficosRESUMEN
Respiratory syncytial virus (RSV) is an important cause of severe respiratory disease in persons at both extremes of age. Wheezing is a cardinal sign of infection and the illness is associated with an increased incidence of childhood asthma. Data from both humans and animal models have linked severe disease in infants and the syndrome of vaccine-enhanced illness with an aberrant composition of CD4+ T cells, suggestive of an exaggerated Th2 response. Studies in murine models have shown that prior vaccination, coexisting allergic inflammation, or direct modulation of the cytokine milieu can profoundly influence the immune response to RSV and thereby affect the expression of disease. In addition, there are intrinsic antigenic properties of the RSV G glycoprotein that promote Th2 responses and eosinophilia. This paper proposes an integrated working model of how host and virus factors interact to determine the characteristics of RSV-induced illness. This model suggests strategies for the development of new vaccine and immunotherapeutic interventions, and creates a framework for asking additional questions about the immunopathogenesis of RSV.
Asunto(s)
Asma/inmunología , Citocinas/inmunología , Glicoproteínas/inmunología , Pulmón/inmunología , Eosinofilia Pulmonar/inmunología , Infecciones por Virus Sincitial Respiratorio/inmunología , Animales , Humanos , Pulmón/patologíaRESUMEN
Respiratory syncytial virus (RSV)-induced disease is associated with recurrent episodes of wheezing in children, and an effective vaccine currently is not available. The use of 2 immunizations (a formalin-inactivated, alum-precipitated RSV vaccine [FI-RSV] given intramuscularly and live RSV given intranasally [LVIN]), with a control immunization, were compared in a well-characterized model of RSV challenge, with or without concomitant allergic sensitization with ovalbumin. FI-RSV caused a significant increase in airway hyperresponsiveness in mice after RSV infection during allergic sensitization, and this was associated with an increase in type 2 cytokine production. In contrast, immunization with LVIN did not change type 2 cytokine production and protected against RSV-induced airway hyperresponsiveness in the setting of allergic sensitization. This study suggests that immune modulation with RSV vaccination can have profound effects on RSV-induced airway disease and that prevention of airway hyperresponsiveness is an important end point in vaccine development.
Asunto(s)
Hipersensibilidad Respiratoria/inmunología , Virus Sincitiales Respiratorios/inmunología , Vacunas de Productos Inactivados/inmunología , Vacunas Virales/inmunología , Administración Intranasal , Animales , Modelos Animales de Enfermedad , Femenino , Formaldehído , Cloruro de Metacolina , Ratones , Ratones Endogámicos BALB C , Hipersensibilidad Respiratoria/inducido químicamente , Hipersensibilidad Respiratoria/virología , Infecciones por Virus Sincitial Respiratorio/inmunología , Virus Sincitiales Respiratorios/efectos de los fármacos , Vacunas de Productos Inactivados/administración & dosificación , Vacunas Virales/administración & dosificaciónRESUMEN
OBJECTIVE: To determine the association between mediastinal fibrosis and human leukocyte antigen (HLA) genes. DESIGN: Case-control study. SETTING: Vanderbilt University Medical Center. SUBJECTS: Nineteen consecutive patients with mediastinal fibrosis who presented to the pulmonary clinic at Vanderbilt University Medical Center from 1987 to 1996. The control subjects were 21,086 whites who were cadaveric kidney donors from October 1987 through December 1993. MEASUREMENTS: HLA testing was performed on blood samples from all 19 cases. Information on HLA typing for the control subjects was obtained from the United Network for Organ Sharing. Frequency of HLA class I and II antigens found in the cases was compared with the frequency in the control subjects. RESULTS: The relative risk of mediastinal fibrosis among subjects with the HLA-A2 antigen was 3.32 times that of those who lacked this antigen (95% confidence interval, 1.19 to 9. 2). CONCLUSION: HLA-A2 was strongly associated with mediastinal fibrosis, suggesting that an abnormal immune response is important in the pathogenesis of this disease. Key words: Histoplasma capsulatum; human leukocyte antigen-A2; mediastinal fibrosis
Asunto(s)
Antígeno HLA-A2/genética , Enfermedades del Mediastino/inmunología , Adolescente , Adulto , Estudios de Casos y Controles , Femenino , Fibrosis/diagnóstico , Fibrosis/genética , Fibrosis/inmunología , Frecuencia de los Genes/genética , Antígenos de Histocompatibilidad Clase I/genética , Antígenos de Histocompatibilidad Clase II/genética , Prueba de Histocompatibilidad , Histoplasmosis/diagnóstico , Histoplasmosis/genética , Histoplasmosis/inmunología , Humanos , Masculino , Enfermedades del Mediastino/diagnóstico , Enfermedades del Mediastino/genética , Persona de Mediana Edad , RiesgoRESUMEN
Asthma is a worldwide problem, with more than 17 million persons in the United States estimated to have asthma, and there is evidence that the prevalence is increasing. This article reviews the latest epidemiologic evidence for an increase in asthma prevalence and morbidity, and the evidence that environment plays a significant role in this disease. This review focuses on five specific areas: prevalence, incidence, natural history, environmental factors, and morbidity and mortality.
Asunto(s)
Asma/epidemiología , Adolescente , Adulto , Anciano , Contaminación del Aire/efectos adversos , Asma/etiología , Asma/mortalidad , Asma/fisiopatología , Niño , Preescolar , Femenino , Salud Global , Hospitalización/estadística & datos numéricos , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Prevalencia , Estados Unidos/epidemiologíaRESUMEN
Viral infections have become increasingly recognized as a significant cause of asthma exacerbations, mainly because of improved viral detection techniques. Unfortunately, the ability to specifically treat viral infections and to limit the asthma morbidity associated with these agents has not kept pace with diagnostic technology. This article focuses on current concepts of the epidemiology of viruses in asthma exacerbations, investigations studying the physiologic and immunologic consequences of viral infection, and potential therapies to minimize virally-induced airway hyperresponsiveness. To impact this significant health problem, researchers must definitively ascertain the mechanisms by which viruses induce airway reactivity and must develop rational, safe approaches to prevent the consequences of viral infection in the patient with asthma.
Asunto(s)
Asma/virología , Infecciones por Virus ARN , Estado Asmático/virología , Adolescente , Adulto , Antivirales/uso terapéutico , Asma/tratamiento farmacológico , Asma/inmunología , Asma/fisiopatología , Hiperreactividad Bronquial/tratamiento farmacológico , Hiperreactividad Bronquial/inmunología , Hiperreactividad Bronquial/fisiopatología , Hiperreactividad Bronquial/virología , Niño , Preescolar , Humanos , Lactante , Persona de Mediana Edad , Infecciones por Virus ARN/diagnóstico , Infecciones por Virus ARN/tratamiento farmacológico , Infecciones por Virus ARN/inmunología , Infecciones por Virus ARN/fisiopatología , Estado Asmático/tratamiento farmacológico , Estado Asmático/inmunología , Estado Asmático/fisiopatologíaRESUMEN
Many bacterial toxins, including pertussis toxin (PT), exert potent adjuvant effects on antibody synthesis to coadministered antigens. In these studies, we examined whether locally or peripherally administered PT similarly altered the antibody isotype selection to replicating virus after intranasal (inl) challenge. Mice primed intramuscularly with PT and inl with respiratory syncytial virus (RSV) produced RSV-specific antibodies of the IgG2a isotype at a level similar to that of unprimed controls, with some increase in IgG1 production. Mice primed inl with both PT and RSV showed elevated RSV-specific IgG1, increased serum IgE levels, and increased interleukin (IL)-4 in lung supernatants. Splenocytes from these animals produced increased IL-4 when stimulated in vitro with RSV or PT antigens after infection. These results suggest that PT can influence the local production of IL-4 to alter the humoral and cellular immune responses to viral infection as well as to coadministered antigens.
Asunto(s)
Isotipos de Inmunoglobulinas/biosíntesis , Toxina del Pertussis , Infecciones por Virus Sincitial Respiratorio/inmunología , Virus Sincitial Respiratorio Humano/inmunología , Factores de Virulencia de Bordetella/inmunología , Administración Intranasal , Animales , Anticuerpos Antivirales/biosíntesis , Anticuerpos Antivirales/sangre , Formación de Anticuerpos/efectos de los fármacos , Vacuna contra Difteria, Tétanos y Tos Ferina/inmunología , Inmunoglobulina G/biosíntesis , Inmunoglobulina G/sangre , Isotipos de Inmunoglobulinas/sangre , Ratones , Ratones Endogámicos BALB C , Virus Sincitial Respiratorio Humano/fisiología , Factores de Virulencia de Bordetella/farmacología , Replicación Viral/efectos de los fármacosRESUMEN
Severe respiratory syncytial virus (RSV)-induced disease is associated with childhood asthma and atopy. We combined models of allergen sensitization and RSV infection to begin exploring the immunologic interactions between allergic and virus-induced airway inflammation and its impact on airway hypersensitivity. Airway resistance was measured after methacholine challenge in tracheally intubated mice by whole body plethysmography. Lung inflammation was assessed by bronchoalveolar lavage (BAL) and histopathology. RSV infection alone did not cause significant airway hyperresponsiveness (AHR) to methacholine. Ovalbumin (OVA)-induced AHR lasted only a few days past the discontinuance of OVA aerosol in mice that were ovalbumin sensitized and mock infected. In contrast, OVA-sensitized mice infected with RSV during the OVA aerosol treatments (OVA/RSV) had AHR for more than 2 weeks after infection. However, 2 weeks after either RSV or mock infection, OVA/RSV mice had significantly more lymphocytes found during BAL than OVA mice, whereas the OVA and OVA/RSV groups had the same number of eosinophils. Histopathologic analysis confirmed an increased inflammation in the lungs of OVA/RSV mice compared with OVA mice. In addition, OVA/RSV mice had a more widespread distribution of mucus in their airways with increased amounts of intraluminal mucus pools compared with the other groups. Thus, prolonged AHR in RSV-infected mice during ovalbumin-sensitization correlates with increased numbers of lymphocytes in BAL fluid, increased lung inflammation, and mucus deposition in the airways, but not with airway eosinophilia. A further understanding of the immunologic consequences of combined allergic and virus-induced airway inflammation will impact the management of diseases associated with airway hyperreactivity.