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BACKGROUND: Subsets of patients with severe asthma remain symptomatic despite prolonged, high-dose glucocorticoid therapy. We hypothesized that the clinical glucocorticoid sensitivity of these asthmatics is reflected in differences in peripheral blood dendritic cell subsets. OBJECTIVE: To compare peripheral blood leucocyte populations using flow cytometry at baseline and after 2 weeks of systemic glucocorticoid (steroid) treatment to identify immunological differences between steroid-sensitive (SS) and steroid-resistant (SR) asthmatics. METHODS: Adult severe asthmatics (SS n = 12; SR n = 23) were assessed for their response to 2 weeks of therapy with oral prednisolone. Peripheral blood was obtained before and after therapy and stained for lymphocyte (CD3, CD19, CD4, CD8 and Foxp3) and dendritic cell markers (Lineage negative [CD3, CD14, CD16, CD19, CD20, CD56], HLA-DR+, CD304, CD11c, ILT3 and CD86). RESULTS: A higher median frequency of myeloid DCs (mDCs) but not plasmacytoid DCs (pDCs) was observed in the blood of SR as compared to SS asthmatics (P = .03). Glucocorticoid therapy significantly increased median B cell, but not T cell numbers in both cohorts, with a trend for increased numbers of Foxp3+ Tregs in SS (P = .07), but not SR subjects. Oral prednisolone therapy significantly reduced the median numbers and frequencies of total DCs and pDCs in both SS and SR asthmatics. Interestingly, the expression of HLA-DR and ILT3 was also reduced on pDCs in all patients. In contrast, therapy increased the median frequency of mDCs in SS, but reduced it in SR asthmatics. CONCLUSIONS: Myeloid DC frequency is elevated in SR compared with SS asthmatics, and mDC shows a differential response to oral prednisolone therapy.
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Antígenos CD/inmunología , Células Dendríticas/inmunología , Glucocorticoides/administración & dosificación , Prednisolona/administración & dosificación , Linfocitos T/inmunología , Administración Oral , Adulto , Asma/tratamiento farmacológico , Asma/inmunología , Asma/patología , Células Dendríticas/patología , Femenino , Citometría de Flujo , Humanos , Masculino , Linfocitos T/patologíaRESUMEN
BACKGROUND: Designing biologically informative models for assessing the safety of novel agents, especially for cancer immunotherapy, carries substantial challenges. The choice of an in vivo system for studies on IgE antibodies represents a major impediment to their clinical translation, especially with respect to class-specific immunological functions and safety. Fcε receptor expression and structure are different in humans and mice, so that the murine system is not informative when studying human IgE biology. By contrast, FcεRI expression and cellular distribution in rats mirror that of humans. METHODS: We are developing MOv18 IgE, a human chimeric antibody recognizing the tumour-associated antigen folate receptor alpha. We created an immunologically congruent surrogate rat model likely to recapitulate human IgE-FcεR interactions and engineered a surrogate rat IgE equivalent to MOv18. Employing this model, we examined in vivo safety and efficacy of antitumour IgE antibodies. RESULTS: In immunocompetent rats, rodent IgE restricted growth of syngeneic tumours in the absence of clinical, histopathological or metabolic signs associated with obvious toxicity. No physiological or immunological evidence of a "cytokine storm" or allergic response was seen, even at 50 mg/kg weekly doses. IgE treatment was associated with elevated serum concentrations of TNFα, a mediator previously linked with IgE-mediated antitumour and antiparasitic functions, alongside evidence of substantially elevated tumoural immune cell infiltration and immunological pathway activation in tumour-bearing lungs. CONCLUSION: Our findings indicate safety of MOv18 IgE, in conjunction with efficacy and immune activation, supporting the translation of this therapeutic approach to the clinical arena.
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Anticuerpos Monoclonales de Origen Murino/efectos adversos , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Inmunoglobulina E/efectos adversos , Inmunoglobulina E/uso terapéutico , Inmunoterapia/métodos , Neoplasias/terapia , Receptores de IgE/metabolismo , Animales , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Anticuerpos Monoclonales de Origen Murino/metabolismo , Línea Celular Tumoral , Receptor 1 de Folato/inmunología , Humanos , Inmunoglobulina E/administración & dosificación , Inmunoglobulina E/inmunología , Inmunoglobulina G/inmunología , Inmunoglobulina G/metabolismo , Ratones , Modelos Animales , Neoplasias/patología , Unión Proteica , Ratas , Estadísticas no Paramétricas , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/sangreRESUMEN
Lung cancer is the leading cause of cancer-related morbidity and mortality worldwide. Interaction of nascent or established lung tumour cells with various cytokines and infiltrating immune cells has been implicated in lung cancer pathogenesis. In this study, we systematically analysed immunoreactivity for IL-17A, IL-17E and IL-17F and their relevant receptors in the lung sections from non-small cell lung cancer (NSCLC) and normal control. Immunoreactivity for IL-17A, IL-17F, IL-17RA and IL- 17RC, but not IL-17RB was significantly elevated in NSCLC compared with controls, while IL-17E was reduced. The median numbers of infiltrating lymphocytes and neutrophils and global macrophage (CD68) immunoreactivity of phagocytes were also elevated in NSCLC compared with control tissue sections. Furthermore, correlation between the expression of IL-17A and its receptors IL-17RA and IL- 17RC varied according to NSCLC histopathological type. These data suggest that IL-17A, E, F and their receptors IL-17RA, RB, RC may be involved in the pathogenesis of NSCLC. Further understanding of the relationship between the IL-17/IL-17R axis and the tumour inflammatory microenvironment may reveal new therapeutic targets.
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Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Interleucina-17/clasificación , Interleucina-17/metabolismo , Neoplasias Pulmonares/metabolismo , Receptores de Interleucina-17/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Humanos , Neoplasias Pulmonares/patología , Microambiente TumoralRESUMEN
BACKGROUND: Mild asthmatics who smoke cigarettes may develop unstable disease and neutrophilic infiltration of the airways, features more usually associated with severe asthmatic disease. The mechanisms giving rise to this response remain unclear. OBJECTIVE: To address the hypothesis that smoking increases bronchial mucosal production of IL-17A which acts on bronchial epithelial cells directly and in concert with other environmental stimuli to induce the production of IL-6 and neutrophil chemotaxins. METHODS: IL-17A, IL-8, IL-6, neutrophils and eosinophils were detected and quantified by immunohistochemistry in endobronchial biopsy sections from smoking and non-smoking asthmatics. Human tracheal epithelial cells (HTEpC) were cultured with IL-17A in the presence/absence of cigarette smoke extract (CSE) and aeroallergens lacking intrinsic protease activity, and IL-6 and IL-8 production measured in vitro. RESULTS: Expression of IL-17A, IL-6 and IL-8 and neutrophil numbers was significantly elevated in the bronchial mucosa of the asthmatic smokers compared to the non-smokers. Expression of IL-17A correlated with that of IL-8 and neutrophil numbers. In the smoking asthmatics, eosinophil numbers also correlated with expression of IL-8 and IL-17A. Exposure of HTEpC cells to both CSE and IL-17A increased expression of IL-6 and IL-8 in a concentration-dependent and synergistic manner. Co-stimulation with CSE, IL-17A and aeroallergens further increased IL-6 and IL-8 production synergistically. CONCLUSIONS: The data support the hypothesis that asthmatic smokers develop neutrophilic inflammation of the airways propagated at least partly by smoke-induced production of IL-17A which together with smoke and other environmental stimuli acts on airways epithelial cells to induce neutrophil chemotaxins.
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Asma/inmunología , Fumar Cigarrillos/efectos adversos , Interleucina-17/biosíntesis , Infiltración Neutrófila/inmunología , Mucosa Respiratoria/inmunología , Adolescente , Adulto , Alérgenos/inmunología , Asma/patología , Bronquios/inmunología , Bronquios/patología , Fumar Cigarrillos/inmunología , Exposición a Riesgos Ambientales/efectos adversos , Humanos , Inflamación/inmunología , Inflamación/patología , Mucosa Respiratoria/patología , Adulto JovenRESUMEN
BACKGROUND: RELM-ß has been implicated in airways inflammation and remodelling in murine models. Its possible functions in human airways are largely unknown. The aim was to address the hypothesis that RELM-ß plays a role in extracellular matrix deposition in asthmatic airways. METHODS: The effects of RELM-ß gene deficiency were studied in a model of allergen exposure in mice sensitised and challenged with Aspergillus fumigatus (Af). RELM-ß expression was investigated in bronchial biopsies from asthmatic patients. Direct regulatory effects of RELM-ß on human lung fibroblasts were examined using primary cultures and the MRC5 cell line in vitro. RESULTS: Sensitisation and challenge of wild-type mice with Af-induced release of RELM-ß with a time course coincident with that of procollagen in the airways. Af-induced expression of mRNA encoding some, but not all ECM in the lung parenchyma was attenuated in RELM-ß-/- mice. RELM-ß expression was significantly increased in the bronchial submucosa of human asthmatics compared with controls, and its expression correlated positively with that of fibronectin and α-smooth muscle actin. In addition to epithelial cells, macrophages, fibroblasts and vascular endothelial cells formed the majority of cells expressing RELM-ß in the submucosa. Exposure to RELM-ß increased TGF-ß1, TGF-ß2, collagen I, fibronectin, smooth muscle α-actin, laminin α1, and hyaluronan and proteoglycan link protein 1 (Hapl1) production as well as proliferation by human lung fibroblasts in vitro. These changes were associated with activation of ERK1/2 in MRC5 cells. CONCLUSION: The data are consistent with the hypothesis that elevated RELM-ß expression in asthmatic airways contributes to airways remodelling at least partly by increasing fibroblast proliferation and differentiation with resulting deposition of extracellular matrix proteins.
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Remodelación de las Vías Aéreas (Respiratorias) , Asma/metabolismo , Asma/patología , Fibroblastos/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Mucosa Respiratoria/metabolismo , Mucosa Respiratoria/patología , Actinas/metabolismo , Remodelación de las Vías Aéreas (Respiratorias)/genética , Remodelación de las Vías Aéreas (Respiratorias)/inmunología , Animales , Asma/inmunología , Líquido del Lavado Bronquioalveolar , Proliferación Celular , Colágeno/metabolismo , Modelos Animales de Enfermedad , Matriz Extracelular , Genotipo , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Laminina/metabolismo , Ratones , Ratones Noqueados , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Fosforilación , Mucosa Respiratoria/inmunología , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Crecimiento Transformador beta2/metabolismoRESUMEN
BACKGROUND: Interleukin-25 has been implicated in the pathogenesis of asthma from studies on human asthmatics and in murine asthma models. OBJECTIVES: In this study, we hypothesized that chronic exposure of the airways to IL-25 alone is able to induce pathogenic changes observed in animal models of asthma. METHODS: We performed a detailed comparison of the dynamics of development of cellular infiltration, cytokine expression and airways remodelling and hyperresponsiveness in mice sensitized and challenged with OVA, a classical model of allergic asthma and those exposed to IL-25 alone. RESULTS: Intranasal challenge of BALB/c mice with IL-25 alone induced a delayed (compared with OVA-challenge), predominantly eosinophilic and lymphocytic infiltration into the airways lumen, along with increased production of Th2-type cytokines, chemokines and collagen, secretion of epithelial mucus, goblet cell hyperplasia, deposition of subepithelial collagen, airways smooth muscle cell hyperplasia and angiogenesis. Correspondingly, IL-25 as well as OVA challenge both induced airways hyperresponsiveness and increased lung tissue damping. In contrast, IL-25 exposure did not increase IgE or IgG1 production. CONCLUSIONS AND CLINICAL RELEVANCE: The data suggest that chronic airways exposure to IL-25 alone is sufficient to induce allergen- and IgE-independent, asthma-like airways inflammation, remodelling and hyperresponsiveness in mice. Thus, IL-25 is a key molecular target in asthma, irrespective of the coexistence of IgE-dependent mechanisms.
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Remodelación de las Vías Aéreas (Respiratorias)/inmunología , Alérgenos/inmunología , Asma/inmunología , Asma/patología , Interleucinas/inmunología , Alérgenos/administración & dosificación , Animales , Asma/metabolismo , Quimiocinas/metabolismo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Eosinofilia/inmunología , Proteínas de la Matriz Extracelular/metabolismo , Femenino , Células Caliciformes/inmunología , Células Caliciformes/patología , Hiperplasia , Hipertrofia , Inmunoglobulina E/inmunología , Inmunoglobulina G/inmunología , Inflamación/inmunología , Inflamación/patología , Interleucinas/administración & dosificación , Pulmón/inmunología , Pulmón/patología , Ratones , Músculo Liso/patologíaRESUMEN
BACKGROUND: Increased proliferation of airway smooth muscle (ASM) cells leading to hyperplasia and increased ASM mass is one of the most characteristic features of airway remodelling in asthma. A bioactive lipid, sphingosine-1-phosphate (S1P), has been suggested to affect airway remodelling by stimulation of human ASM cell proliferation. OBJECTIVE: To investigate the effect of S1P on signalling and regulation of gene expression in ASM cells from healthy and asthmatic individuals. METHODS: Airway smooth muscle cells grown from bronchial biopsies of healthy and asthmatic individuals were exposed to S1P. Gene expression was analysed using microarray, real-time PCR and Western blotting. Receptor signalling and function were determined by mRNA knockdown and intracellular calcium mobilization experiments. RESULTS: S1P potently regulated the expression of more than 80 genes in human ASM cells, including several genes known to be involved in the regulation of cell proliferation and airway remodelling (HBEGF, TGFB3, TXNIP, PLAUR, SERPINE1, RGS4). S1P acting through S1P2 and S1P3 receptors activated intracellular calcium mobilization and extracellular signal-regulated and Rho-associated kinases to regulate gene expression. S1P-induced responses were not inhibited by corticosteroids and did not differ significantly between ASM cells from healthy and asthmatic individuals. CONCLUSION: S1P induces a steroid-resistant, pro-remodelling pathway in ASM cells. Targeting S1P or its receptors could be a novel treatment strategy for inhibiting airway remodelling in asthma.
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Remodelación de las Vías Aéreas (Respiratorias)/efectos de los fármacos , Lisofosfolípidos/farmacología , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Esfingosina/análogos & derivados , Corticoesteroides/farmacología , Remodelación de las Vías Aéreas (Respiratorias)/genética , Asma/genética , Asma/metabolismo , Asma/patología , Bronquios/efectos de los fármacos , Bronquios/metabolismo , Bronquios/patología , Calcio/metabolismo , Estudios de Casos y Controles , Células Cultivadas , Análisis por Conglomerados , Resistencia a Medicamentos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Receptores de Lisoesfingolípidos/genética , Receptores de Lisoesfingolípidos/metabolismo , Transducción de Señal , Esfingosina/farmacología , Receptores de Esfingosina-1-Fosfato , Quinasas Asociadas a rho/metabolismoRESUMEN
Several epidemiological studies have evaluated potential associations between allergy and risk of malignancy. It remains clear that the relationship between allergy and cancer is complex. Three hypotheses have been proposed to account for observed relationships: these are chronic inflammation, immunosurveillance, prophylaxis, and we propose adding a fourth: inappropriate T-helper 2 (Th2) immune skewing. Each of these attempts to explain either the increased or decreased risk of different cancer types in 'allergic' patients reported in the literature. All four hypotheses are based on known mechanisms of allergic inflammation and/or IgE antibody functions, and uphold the view of an immunological basis for the relationship between allergy and malignancies. This review summarizes and draws conclusions from the epidemiological literature examining the relationships between specific types of cancer and allergic diseases. Particular emphasis is placed on the most recent contributions to the field, and on consideration of the allergic immune mechanisms that may influence positive or negative associations.
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Hipersensibilidad/complicaciones , Inmunoglobulina E/inmunología , Neoplasias/etiología , Transformación Celular Neoplásica/inmunología , Humanos , Hipersensibilidad/inmunología , Neoplasias/epidemiología , Neoplasias/inmunología , RiesgoRESUMEN
Though implicated in vascular remodelling, a role for the resistin-like molecule (RELM)-ß in human airway remodelling remains unexplored. We hypothesised that RELM-ß expression is increased in the airways of asthmatics and regulates airways epithelial cell function. Expression of RELM-ß in the bronchial mucosa and its concentrations in bronchoalveolar lavage (BAL) fluid from asthmatics and controls were measured by immunohistochemistry and ELISA, respectively. Proliferation assays, Western blotting, ELISA and real-time PCR were employed to detect effects of RELM-ß on airways epithelial cells. RELM-ß expression was increased in the bronchial mucosa and BAL fluid of asthmatics compared with controls. In the asthmatics, the numbers of mucosal RELM-ß+ cells correlated inversely with forced expiratory volume in 1 s (r=-0.531, p=0.016), while the numbers of epithelial RELM-ß+ cells correlated positively with those of mucin (MUC)5AC+ cells. In vitro, interleukin-13 enhanced RELM-ß expression by primary human airways epithelial cells, while RELM-ß itself acted on these cells to induce proliferation, expression of MUC5AC, extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK)-phosphatidylinositol 3-kinase (PI3K)/Akt phosphorylation and elevated expression of transforming growth factor-ß2, epidermal growth factor and vascular endothelial growth factor. RELM-ß has the potential to contribute to airway remodelling in diseases such as asthma by acting on epithelial cells to increase proliferation, mucin and growth factor production, at least partly via ERK/MAPK-PI3K/Akt signalling pathways.
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Asma/fisiopatología , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Mucosa Respiratoria/fisiología , Adulto , Asma/patología , Líquido del Lavado Bronquioalveolar , División Celular/fisiología , Células Cultivadas , Factor de Crecimiento Epidérmico/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mucina 5AC/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación/fisiología , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Mensajero/metabolismo , Mucosa Respiratoria/citología , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Crecimiento Transformador beta2/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
BACKGROUND: Unlike other IL-17 family members, the Th2-derived cytokine IL-25 (IL-17E) induces (promotes) Th2 responses. One or both of the two receptors for IL-25 (IL-17RA, IL-17RB) is expressed on inflammatory cells and tissue structural cells, suggesting that in addition to promoting Th2-type inflammation IL-25 may also act on structural cells at sites of Th2-type inflammation such as in the asthmatic bronchial mucosa to promote remodelling changes. OBJECTIVE: Our previous studies showed elevated expression of IL-25 and IL-17RB immunoreactivity in asthmatic airways with co-localization of the latter to endothelial cells. We therefore hypothesized that IL-25 acts on endothelial cells through this receptor to induce production of the key angiogenic and remodelling cytokine basic fibroblast growth factor (bFGF). METHODS: Polymerase chain reaction (PCR) immunocytochemistry/immunohistochemistry and ELISA were employed to detect expression of IL-17RB, IL-17RA and bFGF by human vascular endothelial cells (HUVEC) and immunoreactivity for IL-25 and bFGF in asthmatic bronchial biopsies. Receptor-blocking antibodies, PCR and an in vitro angiogenesis assay were used to investigate whether IL-25 acts on IL-17RB or IL-17RA to induce bFGF expression and angiogenesis. PCR was also employed to investigate the signalling pathways involved in IL-25-mediated bFGF expression. RESULTS: HUVEC constitutively expressed IL-17RB, IL-17RA and bFGF. Production of the latter was further increased by IL-25, but attenuated after blockade of the IL-17RB, but not the IL-17RA receptor. Neutralization of endogenous VEGF and bFGF completely abrogated IL-25-induced angiogenesis which was also inhibited by blocking IL-17RB, but not IL-17RA. The PI3K-specific inhibitor LY294002 also completely attenuated IL-25-induced bFGF expression. Immunoreactivity for IL-25 and bFGF was elevated in the asthmatic bronchial mucosa and the expression of each correlated with the other. CONCLUSIONS AND CLINICAL RELEVANCE: Our data support the hypothesis that IL-25 contributes to elevated bFGF in asthmatic airways by acting on the endothelial cell IL-17RB receptor through PI3K-signalling pathways. Targeting the pathways might benefit therapy of airways remodelling.
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Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Interleucina-17/farmacología , Receptores de Interleucina-17/metabolismo , Células Cultivadas , Células Endoteliales/inmunología , Factor 2 de Crecimiento de Fibroblastos/genética , Factor 2 de Crecimiento de Fibroblastos/inmunología , Regulación de la Expresión Génica/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Interleucina-17/inmunología , Neovascularización Fisiológica/efectos de los fármacos , Receptores de Interleucina-17/antagonistas & inhibidores , Receptores de Interleucina-17/genética , Transducción de Señal/efectos de los fármacosRESUMEN
BACKGROUND: Murine models suggest a critical functional role for the anti-inflammatory cytokine IL-10 in local regulation of allergic airways inflammation. There is little corresponding information on human airway cells. This study aimed to investigate whether local IL-10 production regulates responses by respiratory mucosal leucocytes isolated from nasal polyps. MATERIALS AND METHODS: Nasal polyp tissue was harvested from 24 patients sensitised to aeroallergens with chronic rhinitis and polyposis undergoing routine polypectomy. Cells were isolated by matrix proteolysis. Cytokine production by polyp cells was determined by cytometric bead array (CBA) and intracellular cytokine analysis. Surface marker expression by polyp cells was determined by flow cytometry. RESULTS: Allergen stimulation significantly enhanced production of IL-10, but not IL-5 or IFN-γ by nasal polyp cell suspensions. Under the same conditions, neutralisation of IL-10 significantly increased allergen-specific IL-5 and IFN-γ production by nasal polyp cells. Cell depletion experiments showed that T cells themselves were primarily responsible for IL-10 production or for inducing its production by other cells. Intracellular cytokine staining confirmed production of IL-10 in the absence of IL-2 production by T cells in response to allergen. CONCLUSION: T cells within the human respiratory mucosa produce IL-10, which is capable of inhibiting pro-inflammatory Th2 and Th1 cytokine production in an antigen-specific fashion.
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Citocinas/biosíntesis , Leucocitos/inmunología , Pólipos Nasales/inmunología , Mucosa Respiratoria/inmunología , Linfocitos T/inmunología , Células Th2/inmunología , Adolescente , Adulto , Anciano , Alérgenos/inmunología , Citocinas/inmunología , Humanos , Inmunofenotipificación , Interleucina-5/biosíntesis , Interleucina-5/inmunología , Persona de Mediana Edad , Pólipos Nasales/metabolismo , Mucosa Respiratoria/metabolismo , Linfocitos T/metabolismo , Células Th2/metabolismo , Adulto JovenRESUMEN
Allergic rhinitis (AR) affects more than 20% of the population in the United Kingdom and western Europe and represents a major cause of morbidity that includes interference with usual daily activities and impairment of sleep quality. This guidance prepared by the Standards of Care Committee (SOCC) of the British Society for Allergy and Clinical Immunology (BSACI) is for the management of AR in patients that have failed to achieve adequate relief of symptoms despite treatment with intranasal corticosteroids and/or antihistamines. The guideline is based on evidence and is for use by both adult physicians and paediatricians practising allergy. During the development of these guidelines, all BSACI members were included in the consultation process using a web-based system. Their comments and suggestions were carefully considered by the SOCC. Where evidence was lacking, consensus was reached by the experts on the committee. Included in this guideline are indications and contraindications for immunotherapy, criteria for patient selection, the evidence for short- and long-term efficacy of subcutaneous and sublingual immunotherapy, and discussion on safety and the different modes of immunotherapy including, pre-seasonal and co-seasonal treatments. There are sections on children, allergen standardization, vaccines used in the United Kingdom, oral allergy syndrome, cost effectiveness of immunotherapy and practical considerations of undertaking immunotherapy including recommendations on who should undertake immunotherapy and dosing schedules. Finally, there is discussion on potential biomarkers of response to immunotherapy, the use of component-resolved diagnostics, novel approaches, alternative routes and potential areas for future research.
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Desensibilización Inmunológica , Rinitis Alérgica Perenne/terapia , Rinitis Alérgica Estacional/terapia , Administración Cutánea , Administración Sublingual , Adulto , Alérgenos/inmunología , Niño , Contraindicaciones , Análisis Costo-Beneficio , Desensibilización Inmunológica/efectos adversos , Desensibilización Inmunológica/economía , Humanos , Pronóstico , Investigación , Rinitis Alérgica Perenne/diagnóstico , Rinitis Alérgica Estacional/diagnóstico , Resultado del Tratamiento , Reino UnidoRESUMEN
Bronchial mucosal CD8(+) cells are implicated in chronic obstructive pulmonary disease (COPD) pathogenesis, but there are few data on their functional properties. We have developed a novel technique to outgrow these cells from COPD patients in sufficient numbers to examine effector functions. Endobronchial biopsies from 15 COPD smokers and 12 ex-smokers, 11 control smokers and 10 non-smokers were cultured with anti-CD3/interleukin (IL)-2 ± IL-15. Outgrown CD3(+) T cells were characterized in terms of phenotype (expression of CD4, 8, 25, 28, 69 and 56), cytotoxicity and expression of COPD-related cytokines. Compared with IL-2 alone, additional IL-15 increased the yield and viability of biopsy-derived CD3(+) T cells (12-16-day culture without restimulation) without alteration of CD4(+) /CD8(+) ratios or expression of accessory/activation molecules. Biopsy-derived T cells, principally CD8(+)/CD56(+) cells, exhibited statistically significantly greater cytotoxic activity in current or ex-smokers with COPD compared with controls (P < 0·01). Elevated percentages of CD8(+) T cells expressed interferon (IFN)-γ, tumour necrosis factor (TNF)-α and IL-13 (P < 0·01) in current COPD smokers compared with all comparison groups. It is possible to perform functional studies on bronchial mucosal T cells in COPD. We demonstrate increased CD8(+)CD56(+) T cell cytotoxic activity and expression of remodelling cytokines in smokers who develop COPD.
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Citocinas/inmunología , Citotoxicidad Inmunológica/inmunología , Enfermedad Pulmonar Obstructiva Crónica/inmunología , Linfocitos T/inmunología , Adulto , Anciano , Biopsia , Bronquios/inmunología , Bronquios/patología , Complejo CD3/inmunología , Complejo CD3/metabolismo , Técnicas de Cultivo de Célula/métodos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Citocinas/metabolismo , Femenino , Citometría de Flujo , Humanos , Inmunofenotipificación , Interleucina-12/farmacología , Interleucina-15/farmacología , Células K562 , Masculino , Persona de Mediana Edad , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/patología , Mucosa Respiratoria/inmunología , Mucosa Respiratoria/patología , Fumar , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismoRESUMEN
BACKGROUND: Thymic stromal lymphopoietin (TSLP) is an interleukin (IL)-7-like cytokine that triggers dendritic cell-mediated T helper (Th)2 inflammatory responses through a receptor consisting of a heterodimer of the IL-7 receptor alpha (IL-7Ralpha) chain and the TSLP receptor (TSLPR), which resembles the cytokine receptor common gamma chain. Dendritic cells activated by TSLP prime development of CD4(+) T cells into Th2 cells contributing to the pathogenesis of allergic inflammation. We hypothesized that allergen exposure induces expression of TSLP and results in recruitment of TSLPR bearing cells in the cutaneous allergen-induced late-phase reaction (LPR) in atopic subjects. METHODS: Skin biopsies were obtained from atopic subjects (n = 9) at various times after cutaneous allergen challenge. In situ hybridization and immunohistochemistry were used to determine TSLP mRNA expression and to measure infiltration of TSLPR(+) DC in skin LPR. RT-PCR and flow cytometry were employed to analyse TSLPR expression on isolated blood DC. RESULTS: Allergen-induced skin TSLP expression occurred as early as 1 h after allergen challenge, whereas TSLPR(+) and CD11c(+) cells infiltrated relatively late (24-48 h). The majority of TSLPR(+) cells were DC co-expressing blood DC antigen-1 (BDCA-1) or BDCA-2. Freshly isolated blood DC expressed both TSLPR and IL-7Ralpha chains. Maturation and stimulation with TSLP or polyriboinosinic-polyribocytidylic acid in vitro upregulated the expression of both TSLPR and IL-7Ralpha chains in DC but not in chemoattractant receptor-homologous molecule expressed on Th2 cells(+) CD4(+) T cells. CONCLUSION: The data suggest that TSLP plays a role in augmenting, through DC recruitment and activation, the development of Th2-type T cells in allergic inflammation.
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Linfocitos T CD4-Positivos/inmunología , Citocinas/biosíntesis , Células Dendríticas/inmunología , Hipersensibilidad/inmunología , Receptores de Citocinas/metabolismo , Receptores de Interleucina-7/metabolismo , Adolescente , Adulto , Alérgenos/inmunología , Antígenos CD1 , Antígenos de Superficie/inmunología , Antígenos de Superficie/metabolismo , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/metabolismo , Citocinas/inmunología , Citocinas/farmacología , Células Dendríticas/efectos de los fármacos , Células Dendríticas/metabolismo , Glicoproteínas , Humanos , Hipersensibilidad/metabolismo , Inductores de Interferón/farmacología , Interleucina-15/farmacología , Interleucina-7/farmacología , Lectinas Tipo C/inmunología , Lectinas Tipo C/metabolismo , Glicoproteínas de Membrana/inmunología , Glicoproteínas de Membrana/metabolismo , Persona de Mediana Edad , Poli I-C/farmacología , Receptores de Citocinas/agonistas , Receptores de Citocinas/inmunología , Receptores Inmunológicos/inmunología , Receptores Inmunológicos/metabolismo , Receptores de Interleucina-7/agonistas , Receptores de Interleucina-7/inmunología , Piel/inmunología , Piel/patología , Adulto Joven , Linfopoyetina del Estroma TímicoRESUMEN
We have attempted to identify mRNA for IL-5 in endobronchial mucosal biopsies from asthmatics and controls, using the technique of in situ hybridization. Bronchial biopsies were obtained from 10 asthmatics and 9 nonatopic normal controls. A radio-labeled cRNA probe was prepared from an IL-5 cDNA and hybridized to permeabilized sections. These were washed extensively before processing for autoradiography. An IL-5-producing T cell clone derived from a patient with the hyper-IgE syndrome was used as a positive control. As a negative control, sections were also treated with a "sense" IL-5 probe. Specific hybridization signals for IL-5 mRNA were demonstrated within the bronchial mucosa in 6 out of the 10 asthmatic subjects. Cells exhibiting hybridization signals were located beneath the epithelial basement membrane. In contrast, there was no hybridization in the control group. No hybridization was observed with the sense probe. The six IL-5 mRNA-positive asthmatics tended to have more severe disease than the negative asthmatics, as assessed by symptoms and lung function, and showed a significant increase in the degree of infiltration of the bronchial mucosa by secreting (EG2+) eosinophils and activated (CD25+) T lymphocytes. Within the subjects who showed positive IL-5 mRNA, there was a correlation between IL-5 mRNA expression and the number of CD25+ and EG2+ cells and total eosinophil count. This study provides evidence for the cellular localization of IL-5 mRNA in the bronchial mucosa of asthmatics and supports the concept that this cytokine regulates eosinophil function in bronchial asthma.
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Asma/metabolismo , Bronquios/metabolismo , Interleucina-5/genética , ARN Mensajero/análisis , Adulto , Antígenos CD/análisis , Asma/inmunología , Biopsia , Bronquios/inmunología , Femenino , Humanos , Masculino , Membrana Mucosa/metabolismo , Hibridación de Ácido Nucleico , Linfocitos T/inmunologíaRESUMEN
The past year has seen significant advances in several fields of asthma and allergy research. Notable among these advances were the following: the demonstration that inflammatory granulocytes may be a source of cytokines; an increased understanding of the inter-relationships between the inflammatory cells invading the asthmatic bronchial mucosa; some important new approaches to asthma therapy; and the beginnings of a systematic classification of the structure of allergens and their antigenic epitopes.
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Hipersensibilidad Respiratoria/inmunología , Alérgenos/inmunología , Animales , Asma/inmunología , Asma/terapia , Citocinas/inmunología , Granulocitos/inmunología , Humanos , Linfocitos T/inmunologíaRESUMEN
Health professionals tasked with advising patients with asthma and chronic obstructive pulmonary disease (COPD) how to use inhaler devices properly and what to do about unwanted effects will be aware of a variety of commonly held precepts. The evidence for many of these is, however, lacking or old and therefore in need of re-examination. Few would disagree that facilitating and encouraging regular and proper use of inhaler devices for the treatment of asthma and COPD is critical for successful outcomes. It seems logical that the abandonment of unnecessary or ill-founded practices forms an integral part of this process: the use of inhalers is bewildering enough, particularly with regular introduction of new drugs, devices and ancillary equipment, without unnecessary and pointless adages. We review the evidence, or lack thereof, underlying ten items of inhaler 'lore' commonly passed on by health professionals to each other and thence to patients. The exercise is intended as a pragmatic, evidence-informed review by a group of clinicians with appropriate experience. It is not intended to be an exhaustive review of the literature; rather, we aim to stimulate debate, and to encourage researchers to challenge some of these ideas and to provide new, updated evidence on which to base relevant, meaningful advice in the future. The discussion on each item is followed by a formal, expert opinion by members of the ADMIT Working Group.
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Asma/tratamiento farmacológico , Broncodilatadores/administración & dosificación , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Administración por Inhalación , Aerosoles , Diseño de Equipo , Humanos , Nebulizadores y VaporizadoresRESUMEN
[This corrects the article DOI: 10.1038/npjpcrm.2016.17.].
RESUMEN
1. The cyclic AMP phosphodiesterases (PDE) expressed by CD4+ and CD8+ T-lymphocytes purified from the peripheral blood of normal adult subjects were identified and characterized, and their role in modulating proliferation and the biosynthesis of interleukin (IL)-2 and interferon (IFN)-gamma evaluated. 2. In lysates prepared from both subsets, SK&F 95654 (PDE3 inhibitor) and rolipram (PDE4 inhibitor) suppressed cyclic AMP hydrolysis indicating the presence of PDE3 and PDE4 isoenzymes in these cells. Differential centrifugation and subsequent inhibitor and kinetic studies revealed that the particulate fraction contained, predominantly, a PDE3 isoenzyme. In contrast, the soluble fraction contained a PDE4 (approximately 65% of total activity) and, in addition, a novel enzyme that had the kinetic characteristics of the recently identified PDE7. 3. Reverse transcription-polymerase chain reaction (RT-PCR) studies with primer pairs designed to recognise unique sequences in the human PDE4 and PDE7 genes amplified cDNA fragments that corresponded to the predicted sizes of HSPDE4A, HSPDE4B, HSPDE54D and HSPDE7. No message was detected for HSPDE4C after 35 cycles of amplification. 4. Functionally, rolipram inhibited phytohaemagglutinin- (PHA) and anti-CD3-induced proliferation of CD4+ and CD8+ T-lymphocytes, and the elaboration of IL-2, which was associated with a three to four fold increase in cyclic AMP mass. In all experiments, however, rolipram was approximately 60 fold more potent at suppressing IL-2 synthesis than at inhibiting mitogenesis. In contrast, SK&F 95654 failed to suppress proliferation and cytokine generation, and did not elevate the cyclic AMP content in T-cells. Although inactive alone, SK&F 95654 potentiated the ability of rolipram to suppress PHA- and anti-CD3-induced T-cell proliferation, and PHA-induced IL-2 release. 5. When a combination of phorbol myristate acetate (PMA) and ionomycin were used as a co-mitogen, rolipram did not affect proliferation but, paradoxically, suppressed IL-2 release indicating that cyclic AMP can inhibit mitogenesis by acting at, or proximal to, the level of inositol phospholipid hydrolysis. 6. Collectively, these data suggest that PDE3 and PDE4 isoenzymes regulate the cyclic AMP content, IL-2 biosynthesis and proliferation in human CD4+ and CD8+ T-lymphocytes. However, the ability of rolipram to suppress markedly mitogen-induced IL-2 generation without affecting T-cell proliferation suggests that growth and division of T-lymphocytes may be governed by mediators in addition to IL-2. Finally, T-cells have the potential to express PDE7, although elucidating the functional role of this enzyme must await the development of selective inhibitors.