RESUMEN
Levels of cytokines are used for in-depth characterization of patients with asthma; however, the variability over time might be a critical confounder. To analyze the course of serum cytokines in children, adolescents and adults with asthma and in healthy controls and to propose statistical methods to control for seasonal effects. Of 532 screened subjects, 514 (91·5%) were included in the All Age Asthma Cohort (ALLIANCE). The cohort included 279 children with either recurrent wheezing bronchitis (more than two episodes) or doctor-diagnosed asthma, 75 healthy controls, 150 adult asthmatics and 31 adult healthy controls. Blood samples were collected and 25 µl serum was used for analysis with the Bio-Plex Pr human cytokine 27-Plex assay. Mean age, body mass index and gender in the three groups of wheezers, asthmatic children and adult asthmatics were comparable to healthy controls. Wheezers (34·5%), asthmatic children (78·7%) and adult asthmatics (62·8%) were significantly more often sensitized compared to controls (4·5, 22 and 22·6%, respectively). Considering the entire cohort, interleukin (IL)-1ra, IL-4, IL-9, IL-17, macrophage inflammatory protein (MIP)-1- α and tumor necrosis factor (TNF)- α showed seasonal variability, whereas IL-1ß, IL-7, IL-8, IL-13, eotaxin, granulocyte colony-stimulating factor (G-CSF), interferon gamma-induced protein (IP)-10, MIP-1 ß and platelet-derived growth factor (PDGF)-BB did not. Significant differences between wheezers/asthmatics and healthy controls were observed for IL-17 and PDGF-BB, which remained stable after adjustment for the seasonality of IL-17. Seasonality has a significant impact on serum cytokine levels in patients with asthma. Because endotyping has achieved clinical importance to guide individualized patient-tailored therapy, it is important to account for seasonal effects.
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Asma/inmunología , Citocinas/inmunología , Ruidos Respiratorios/inmunología , Estaciones del Año , Adolescente , Adulto , Algoritmos , Asma/sangre , Asma/diagnóstico , Niño , Preescolar , Estudios de Cohortes , Citocinas/sangre , Femenino , Humanos , Masculino , Modelos Teóricos , Ruidos Respiratorios/diagnóstico , Factores de TiempoRESUMEN
The Future of the Allergists and Specific Immunotherapy (FASIT) workshop provides a regular platform for global experts from academia, allergy clinics, regulatory authorities and industry to review developments in the field of allergen immunotherapy (AIT). The most recent meeting, held in February 2017, had two main themes: advances in AIT and hot topics in AIT from the regulatory point of view. The first theme covered opportunities for personalized AIT, advances in adjuvants and delivery systems, and the development of new molecules and future vaccines for AIT. Key topics in the second part of the meeting were the effects of the enactment of European Directive 2001/83 on the availability of allergens for therapy and diagnosis across the EU, the challenges of conducting Phase 3 studies in the field, the future role of allergen exposure chambers in AIT studies and specific considerations in performing AIT studies in the paediatric population. Finally, the group highlighted the forthcoming EAACI guidelines and their particular importance for the standardization of practice in the treatment of allergies. This review presents a comprehensive insight into those panel discussions and highlights unmet needs and also possible solutions to them for the future.
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Desensibilización Inmunológica/normas , Desensibilización Inmunológica/tendencias , Hipersensibilidad/diagnóstico , Hipersensibilidad/terapia , Medicina de Precisión/métodos , Vacunología/métodos , Adyuvantes Inmunológicos/uso terapéutico , Adolescente , Adulto , Biomarcadores , Niño , Preescolar , Sistemas de Liberación de Medicamentos/métodos , Descubrimiento de Drogas , Humanos , Terminología como Asunto , Resultado del TratamientoRESUMEN
Recent data suggest a possible relationship between cystic fibrosis (CF) pharmacotherapy, Aspergillus fumigatus colonization (AC) and/or allergic bronchopulmonary aspergillosis (ABPA). The aim of this study was to determine if anti-fungal defence mechanisms are influenced by CF pharmacotherapy, i.e. if (1) neutrophils form CF and non-CF donors differ in their ability to produce chitotriosidase (CHIT-1); (2) if incubation of isolated neutrophils with azithromycin, salbutamol, prednisolone or rhDNase might influence the CHIT-1 activity; and (3) if NETosis and neutrophil killing efficiency is influenced by rhDNase. Neutrophils were isolated from the blood of CF patients (n = 19; mean age 26·8 years or healthy, non-CF donors (n = 20; 38·7 years) and stimulated with phorbol-12-myristate-13-acetate (PMA), azithromycin, salbutamol, prednisolone or rhDNase. CHIT-1 enzyme activity was measured with a fluorescent substrate. NETosis was induced by PMA and neutrophil killing efficiency was assessed by a hyphae recovery assay. Neutrophil CHIT-1 activity was comparable in the presence or absence of PMA stimulation in both CF and non-CF donors. PMA stimulation and preincubation with rhDNase increased CHIT-1 activity in culture supernatants from non-CF and CF donors. However, this increase was significant in non-CF donors but not in CF patients (P < 0·05). RhDNase reduced the number of NETs in PMA-stimulated neutrophils and decreased the killing efficiency of leucocytes in our in-vitro model. Azithromycin, salbutamol or prednisolone had no effect on CHIT-1 activity. Stimulation of isolated leucocytes with PMA and treatment with rhDNase interfered with anti-fungal defence mechanisms. However, the impact of our findings for treatment in CF patients needs to be proved in a clinical cohort.
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Fibrosis Quística/inmunología , Desoxirribonucleasas/uso terapéutico , Hexosaminidasas/metabolismo , Neutrófilos/enzimología , Neutrófilos/patología , Adolescente , Adulto , Anciano , Albuterol/farmacología , Albuterol/uso terapéutico , Aspergillus fumigatus/aislamiento & purificación , Azitromicina/farmacología , Azitromicina/uso terapéutico , Bacterias/aislamiento & purificación , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/microbiología , Desoxirribonucleasas/genética , Trampas Extracelulares/efectos de los fármacos , Femenino , Hongos/aislamiento & purificación , Hexosaminidasas/análisis , Hexosaminidasas/biosíntesis , Humanos , Masculino , Persona de Mediana Edad , Neutrófilos/efectos de los fármacos , Neutrófilos/fisiología , Ésteres del Forbol/farmacología , Prednisolona/farmacología , Prednisolona/uso terapéutico , Esputo/microbiología , Adulto JovenRESUMEN
BACKGROUND: The prevalence of asthma and overweight/obesity in children and adolescents is continuously increasing over the last decades. It remains unclear if overweight/obesity raises the risk of developing asthma or if an uncontrolled asthma increases the risk of developing overweight/obesity by restricting physical activity. OBJECTIVES: We aimed to elucidate, if children and adolescents with overweight/obesity differ from normal-weight asthmatics in lung functions parameters (FEV1, FEV1/VC, MEF50 and SRtot) and in exhaled nitric oxide (FeNO). METHODS: Totally, n=142 children and adolescents aged 6-18 years were included in this study: group 1 comprised n=44 with overweight/obesity defined as a Body-Mass-Index (BMI)>90th percentile; group 2 n=44 with a doctors diagnosed bronchial asthma according to the GINA-guidelines, and group 3 with n=36 pulmonary healthy controls. N=18 children with both asthma and overweight/obesity were excluded from further analysis. We collected data about socio-demographic variables from a standardized questionnaire, bodyplethysmography (FEV1, FEV1/VC, MEF50 and SRtot) and FeNO. RESULTS: Normal-weight children and adolescents with asthma had significantly lower FEV1/VC (Tiffenau-Index 90,9±12,8) and MEF50 (84.0% predicted±27.6) than children with overweight/obesity (97,6±12,4 p=0.001 respectively 99.1±20.9 p=0.001) and healthy controls (98±13,5 p=0,003; 96.7±19.3 p=0.011). Normal weight asthmatics had a significantly higher FeNO (38.3 ppb) than children and adolescents with overweight/obesity (14.0 ppb p=0.014). CONCLUSIONS: Normal-weight children and adolescents with asthma differ significantly both in their lung function parameters as well as in their exhaled nitric oxide concentration from children and adolescents with overweight/obesity. For clinical practice it is important to note that children and adolescents with overweight/obesity have no signs of an obstructive airway diseases and are as resilient as healthy children and adolescents with regard to their lung function. The possible late-onset of asthma symptoms and lung function changes in children and adolescents with overweight/obesity requires further detailed longitudinal studies.
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Asma/diagnóstico , Asma/fisiopatología , Pruebas Respiratorias , Pulmón/fisiopatología , Óxido Nítrico/sangre , Obesidad Infantil/diagnóstico , Obesidad Infantil/fisiopatología , Pruebas de Función Respiratoria , Adolescente , Asma/epidemiología , Niño , Estudios Transversales , Femenino , Humanos , Masculino , Obesidad Infantil/epidemiología , Valores de ReferenciaRESUMEN
BACKGROUND AND METHODS: Omalizumab is a monoclonal anti-IgE-antibody that is used to treat severe allergic asthma. The aim of this review was to evaluate the available evidence in a panel of experts and to provide recommendations on therapy duration with omalizumab. RESULTS: A direct or indirect interaction between omalizumab and IgE production seems likely. Pharmacokinetic-pharmakodynamic models suggest that omalizumab modulates IgE production. This hypothesis is currently investigated in clinical studies. In addition, available evidence suggests that omalizumab mitigates different factors of airway remodeling. However, based on the currently available data, no recommendations can be given in regard to reduction of dosage or discontinuation of omalizumab in long term treated patients. CONCLUSIONS: Currently, neither dose reductions nor treatment withdrawal can be recommended in patients with severe allergic asthma and long term treatment with omalizumab. Clinical studies addressing these issues are being conducted.
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Anticuerpos Antiidiotipos/administración & dosificación , Anticuerpos Antiidiotipos/inmunología , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/inmunología , Asma/tratamiento farmacológico , Asma/inmunología , Hipersensibilidad/tratamiento farmacológico , Hipersensibilidad/inmunología , Inmunoglobulina E/inmunología , Antialérgicos/administración & dosificación , Antialérgicos/inmunología , Antiasmáticos/administración & dosificación , Antiasmáticos/inmunología , Relación Dosis-Respuesta a Droga , Humanos , Omalizumab , Resultado del TratamientoRESUMEN
BACKGROUND: Targeted agents presently available for mutant KRAS metastatic colorectal cancer (mCRC) are bevacizumab and aflibercept. We evaluated the efficacy and safety of conatumumab (an agonistic monoclonal antibody against human death receptor 5) and ganitumab (a monoclonal antibody against the type 1 insulin-like growth factor receptor) combined with standard FOLFIRI chemotherapy as a second-line treatment in patients with mutant KRAS mCRC. PATIENTS AND METHODS: Patients with mutant KRAS metastatic adenocarcinoma of the colon or rectum refractory to fluoropyrimidine- and oxaliplatin-based chemotherapy were randomized 1 : 1 : 1 to receive intravenous FOLFIRI plus conatumumab 10 mg/kg (Arm A), ganitumab 12 mg/kg (Arm B), or placebo (Arm C) Q2W. The primary end point was progression-free survival (PFS). RESULTS: In total, 155 patients were randomized. Median PFS in Arms A, B, and C was 6.5 months (HR, 0.69; P = 0.147), 4.5 months (HR, 1.01; P = 0.998), and 4.6 months, respectively; median overall survival was 12.3 months (HR, 0.89; P = 0.650), 12.4 months (HR, 1.27; P = 0.357), and 12.0 months; and objective response rate was 14%, 8%, and 2%. The most common grade ≥3 adverse events in Arms A/B/C included neutropenia (30%/25%/18%) and diarrhea (18%/2%/10%). CONCLUSIONS: Conatumumab, but not ganitumab, plus FOLFIRI was associated with a trend toward improved PFS. Both combinations had acceptable toxicity.
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Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Proteínas Proto-Oncogénicas/genética , Proteínas ras/genética , Adenocarcinoma/sangre , Adenocarcinoma/mortalidad , Adenocarcinoma/secundario , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores de Tumor/sangre , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Supervivencia sin Enfermedad , Método Doble Ciego , Femenino , Fluorouracilo/administración & dosificación , Genotipo , Humanos , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Irinotecán , Estimación de Kaplan-Meier , Leucovorina/administración & dosificación , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/secundario , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Proteínas Proto-Oncogénicas p21(ras) , Receptores de IgG/genética , Resultado del TratamientoRESUMEN
Exhaled breath contains numerous volatile organic compounds (VOCs) known to be related to lung disease like asthma. Its collection is non-invasive, simple to perform and therefore an attractive method for the use even in young children. We analysed breath in children of the multicenter All Age Asthma Cohort (ALLIANCE) to evaluate if 'breathomics' have the potential to phenotype patients with asthma and wheeze, and to identify extrinsic risk factors for underlying disease mechanisms. A breath sample was collected from 142 children (asthma: 51, pre-school wheezers: 55, healthy controls: 36) and analysed using gas chromatography-mass spectrometry (GC/MS). Children were diagnosed according to Global Initiative for Asthma guidelines and comprehensively examined each year over up to seven years. Forty children repeated the breath collection after 24 or 48 months. Most breath VOCs differing between groups reflect the exposome of the children. We observed lower levels of lifestyle-related VOCs and higher levels of the environmental pollutants, especially naphthalene, in children with asthma or wheeze. Naphthalene was also higher in symptomatic patients and in wheezers with recent inhaled corticosteroid use. No relationships with lung function or TH2 inflammation were detected. Increased levels of naphthalene in asthmatics and wheezers and the relationship to disease severity could indicate a role of environmental or indoor air pollution for the development or progress of asthma. Breath VOCs might help to elucidate the role of the exposome for the development of asthma. The study was registered at ClinicalTrials.gov (NCT02496468).
RESUMEN
This article is the result of consensus reached by a working group of clinical experts in paediatric allergology as well as representatives from an ethical committee and the European Medicine Agency (EMA). The manuscript covers clinical, scientific, regulatory and ethical perspectives on allergen-specific immunotherapy in childhood. Unmet needs are identified. To fill the gaps and to bridge the different points of view, recommendations are made to researchers, to scientific and patient organizations and to regulators and ethical committees. Working together for the benefit of the community is essential. The European Academy of Allergy and Clinical Immunology (EAACI) serves as the platform of such cooperation.
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Desensibilización Inmunológica/métodos , Desensibilización Inmunológica/tendencias , Asma/inmunología , Asma/terapia , Niño , Desensibilización Inmunológica/normas , Hipersensibilidad a los Alimentos/inmunología , Hipersensibilidad a los Alimentos/terapia , Humanos , Guías de Práctica Clínica como Asunto , Rinitis/inmunología , Rinitis/terapiaRESUMEN
The recommendations of the revised guideline Primary Allergy Prevention published in 2009 are summarized and discussed. The updated guidelines do not further recommend reducing house dust mite allergen exposure as a measure of primary prevention. New suggestions include the avoidance of overweight, and reduction of the exposure to indoor and/or outdoor air pollutants. In line with the current guidelines, there is no scientific evidence that prolonged introduction of solid food is an allergy-preventive measure. Consequently, even children with a family history of atopy can introduce solid foods at the beginning of the 5th month. The recommendations on avoiding environmental tobacco smoke, breast feeding over 4 months, avoiding a mold-promoting indoor climate, vaccination according to current recommendations, and avoidance of furry pets (especially cats) in risk babies have remained unchanged.
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Hipersensibilidad/prevención & control , Adolescente , Adulto , Niño , Preescolar , Estudios Transversales , Desensibilización Inmunológica , Hipersensibilidad a los Alimentos/epidemiología , Hipersensibilidad a los Alimentos/etiología , Hipersensibilidad a los Alimentos/prevención & control , Alemania , Humanos , Hipersensibilidad/epidemiología , Hipersensibilidad/etiología , Lactante , Prevención Primaria , Factores de RiesgoRESUMEN
Autoimmune lymphoproliferative syndrome (ALPS) is mainly caused by defects in the CD95 pathway. Raised CD3+TCRαß+CD4-CD8- double negative T cells and impaired T cell apoptosis are hallmarks of the disease. In contrast, the B cell compartment has been less well studied. We found an altered distribution of B cell subsets with raised transitional B cells and reduced marginal zone B cells, switched memory B cells and plasma blasts in most of 22 analyzed ALPS patients. Moreover, 5 out of 66 ALPS patients presented with low IgG and susceptibility to infection revealing a significant overlap between ALPS and common variable immunodeficiency (CVID). In patients presenting with lymphoproliferation, cytopenia, hypogammaglobulinemia and impaired B cell differentiation, serum biomarkers were helpful in addition to apoptosis tests for the identification of ALPS patients. Our observations may indicate a role for apoptosis defects in some diseases currently classified as CVID.
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Síndrome Linfoproliferativo Autoinmune/diagnóstico , Síndrome Linfoproliferativo Autoinmune/inmunología , Linfocitos B/inmunología , Inmunodeficiencia Variable Común/diagnóstico , Inmunodeficiencia Variable Común/inmunología , Proteína Ligando Fas/sangre , Interleucina-10/sangre , Vitamina B 12/sangre , Adolescente , Adulto , Agammaglobulinemia/inmunología , Apoptosis , Biomarcadores/sangre , Niño , Preescolar , Diagnóstico Diferencial , Proteína Ligando Fas/inmunología , Citometría de Flujo , Humanos , Inmunoglobulina G/sangre , Interleucina-10/inmunología , Persona de Mediana Edad , Monocitos/inmunología , Fenotipo , Linfocitos T/inmunología , Vitamina B 12/inmunología , Receptor fas/sangre , Receptor fas/inmunologíaRESUMEN
BACKGROUND: The treatment of allergic asthma by specific immunotherapy (SIT) is hampered by potential side-effects. OBJECTIVE: The aim of this study was to study the effect of omalizumab, a monoclonal anti-IgE antibody, in combination with SIT in patients with seasonal allergic rhinoconjunctivitis (SAR) and co-morbid seasonal allergic asthma (SAA) incompletely controlled by conventional pharmacotherapy. METHODS: A randomized, double-blind, placebo-controlled, multi-centre trial was performed to assess the efficacy and safety of omalizumab (Xolair) vs. placebo in combination with depigmented SIT (Depigoid) during the grass pollen season. Omalizumab or placebo was started 2 weeks before SIT; the whole treatment lasted 18 weeks. Primary endpoint was daily 'symptom load', the sum of daily scores for symptom severity and rescue medication use. RESULTS: A total of 140 patients (age 11-46 years) were randomized; and a total of 130 finished the study. Combination therapy reduced the symptom load by 39% (P=0.0464, Wilcoxon test) over SIT monotherapy. This difference was mainly due to reduced symptom severity (P=0.0044), while rescue medication use did not change significantly. Combination therapy also improved asthma control (Asthma Control Questionnaire, P=0.0295) and quality of life in the case of asthma (Asthma Quality of Life Questionnaire, P=0.0293) and rhinoconjunctivitis (Rhinoconjunctivitis Quality of Life Questionnaire, P=0.0537). Numbers of patients with 'excellent or good' treatment efficacy according to ratings of investigators (75.0% vs. 36.9%) or patients (78.5% vs. 46.1%) were markedly higher in the combination group than under SIT alone. CONCLUSION: Combination of omalizumab with SIT for treatment of patients with SAR and co-morbid SAA was safe and reduced the symptom load in a statistically significant and clinically meaningful manner.
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Anticuerpos Monoclonales/uso terapéutico , Asma/terapia , Conjuntivitis Alérgica/terapia , Desensibilización Inmunológica/métodos , Rinitis Alérgica Estacional/terapia , Adolescente , Adulto , Antialérgicos/uso terapéutico , Anticuerpos Antiidiotipos , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados , Antígenos de Plantas/uso terapéutico , Asma/fisiopatología , Niño , Terapia Combinada/efectos adversos , Desensibilización Inmunológica/efectos adversos , Método Doble Ciego , Femenino , Volumen Espiratorio Forzado/fisiología , Humanos , Masculino , Persona de Mediana Edad , Omalizumab , Extractos Vegetales/uso terapéutico , Polen/química , Calidad de Vida , Pruebas de Función Respiratoria , Resultado del Tratamiento , Adulto JovenRESUMEN
Dominant-negative mutations in STAT-3 have recently been found in the majority of patients with sporadic or autosomal-dominant hyper IgE syndrome (HIES). Since STAT-3 plays a role in B cell development and differentiation, we analyzed memory B cells in 20 patients with HIES, 17 of which had STAT-3 mutations. All but four patients had reduced non-switched and/or class-switched memory B cells. No reduction in these B cell populations was found in 16 atopic dermatitis patients with IgE levels above 1000 KU/L. There was no correlation between the reduction of memory B cells and the ability to produce specific antibodies. Moreover, there was no correlation between the percentage of memory B cells and the infection history. Analysis of memory B cells can be useful in distinguishing patients with suspected HIES from patients with atopic disease, but probably fails to identify patients who are at high risk of infection.
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Linfocitos B/inmunología , Memoria Inmunológica/inmunología , Síndrome de Job/inmunología , Adolescente , Adulto , Anticuerpos Antivirales/sangre , Formación de Anticuerpos , Linfocitos B/patología , Niño , Estudios de Cohortes , ADN/química , ADN/genética , Dermatitis Atópica/genética , Dermatitis Atópica/inmunología , Dermatitis Atópica/patología , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Genotipo , Humanos , Inmunoglobulina E/inmunología , Inmunoglobulina E/metabolismo , Memoria Inmunológica/genética , Síndrome de Job/genética , Síndrome de Job/patología , Masculino , Persona de Mediana Edad , Mutación , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/inmunología , Adulto JovenRESUMEN
OBJECTIVE: We tested a possible relationship between sulphidoleukotriene (SLT) release of cord blood (CB) basophils, a family history of atopy (HA) and subsequent development of atopic eczema. Population and methods A cohort of 86 neonates were involved (48.8% males; 46.5% with a positive HA(+)). CB samples were analysed for in vitro SLT release quantified by ELISA, and in a subgroup for basophilic activation (CD 63 expression) by flow cytometry in response to a positive control (anti-IgE-receptor antibody), an allergen-mix (TOP and PTOP), egg white (EW), egg yolk (EY), and the purified allergens beta-lactoglobulin (BLG) and alpha-lactalbumin (ALA). RESULTS: Median concentrations of SLT were 124.2 (negative), 3871.5 (positive), 123.9 (TOP), 128.5 (PTOP), 113.1 (EW), 108.4 (EY), 125.2 (BLG) and 122.3 (ALA) pg/mL. Groups of HA(+) and HA(-) show no difference in all analysed allergens. An allergen-specific SLT release (defined as SLT>125 pg/mL above individual baseline and a stimulation index >2) was detected in 98% (positive control), 5% (TOP), 7% (BLG), 3% (ALA) and 2% (EW and EY), respectively. After a median observation period of 18 months, n=7 out of 70 children developed an atopic eczema, but we observed no association between CB SLT release (positive response to at least one tested allergen). CONCLUSION: Allergen-specific SLT release is detectable in 15.5% of healthy neonates, irrespective of their family history of atopy. However, early allergen-specific SLT release is not predictive for the development of atopy.
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Alérgenos/inmunología , Basófilos/metabolismo , Dermatitis Atópica/etiología , Sangre Fetal/citología , Hipersensibilidad Inmediata/genética , Leucotrienos/metabolismo , Envejecimiento , Basófilos/inmunología , Estudios de Cohortes , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Humanos , Recién Nacido , Interferón gamma/metabolismo , Interleucina-13/metabolismo , Masculino , Registros Médicos , Concentración Osmolar , Encuestas y CuestionariosRESUMEN
BACKGROUND: The value of probiotics for primary prevention is controversial. Moreover, only little is known about the underlying immunological mechanisms of action. Therefore, we assessed the proliferative response and cytokine release in cultures of isolated mononuclear cells from pregnant women and their neonates supplemented with Lactobacillus GG (LGG) or placebo. METHODS: In a double-blind, placebo-controlled prospective trial, pregnant women with at least one first-degree relative or a partner with an atopic disease were randomly assigned to receive either the probiotic LGG (ATCC 53103; 5 x 10(9) colony-forming units LGG twice daily) or placebo 4-6 weeks before expected delivery, followed by a post-natal period of 6 months. Cord blood mononuclear cells (CBMC) and peripheral blood mononuclear cells (PBMC) of the corresponding mother were isolated from cord blood and peripheral blood (n=68). The proliferative response of CBMC and PBMC was expressed as the stimulation index (SI), which was calculated according to the ratio between the mean counts per minute (c.p.m.) values measured in the wells with stimulated cells and the mean c.p.m. values measured in the wells with unstimulated cells. Additionally, the cytokines IFN-gamma, IL-10 and IL-13 in the cell culture supernatants were measured using the ELISA technique. RESULTS: No difference was observed between the LGG-supplemented group and the placebo group in terms of the proliferative capacity of maternal or neonatal cord blood cells in response to IL-2, beta-lactoglobulin or LGG. In vitro stimulation with LGG resulted in significantly enhanced release of IL-10 and IFN-gamma, compared with cytokine release in unstimulated controls. However, this phenomenon was observed in supernatants of maternal and neonatal MC in both groups, independent of prior supplementation with LGG. CONCLUSION: LGG has in vitro effects on enhanced IL-10 and IFN-gamma release of mononuclear cells. However, supplementation with LGG during pregnancy did not alter the proliferative capacity or cytokine pattern in their recipients.
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Interferón gamma/metabolismo , Interleucina-10/metabolismo , Interleucina-13/metabolismo , Lactobacillus/inmunología , Leucocitos Mononucleares/inmunología , Probióticos/administración & dosificación , Adulto , Proliferación Celular , Células Cultivadas , Estudios de Cohortes , Método Doble Ciego , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Recién Nacido , Interferón gamma/análisis , Interleucina-10/análisis , Interleucina-13/análisis , Leucocitos Mononucleares/metabolismo , Masculino , Madres , Placebos , Valor Predictivo de las Pruebas , Embarazo , Estudios ProspectivosAsunto(s)
Anafilaxia/diagnóstico , Derivados de Hidroxietil Almidón/efectos adversos , Complicaciones Intraoperatorias/diagnóstico , Vértebras Lumbares/cirugía , Meningomielocele/cirugía , Adolescente , Antialérgicos/uso terapéutico , Antibacterianos/administración & dosificación , Antiinflamatorios/uso terapéutico , Cefuroxima/administración & dosificación , Clemastina/uso terapéutico , Diagnóstico Diferencial , Quimioterapia Combinada , Humanos , Derivados de Hidroxietil Almidón/administración & dosificación , Infusiones Intravenosas , Masculino , Prednisolona/uso terapéuticoRESUMEN
OBJECTIVE: The aim of our study was to conduct a prospective investigation into the potential association of cord blood proliferative response and cytokine production in response to various stimuli on the development of atopic dermatitis (AD) at the age of 3 years. METHODS: Cord blood mononuclear cells (CBMC) from 40 healthy term neonates were isolated. The proliferative response of CBMC stimulated with IL-2, betalactoglobulin (BLG) and house dust mite allergen (Der p 1) was assessed by liquid scintillation counting and the stimulation index (SI) was calculated. The cytokines interleukin (IL-)13, interferon (IFN-)gamma, IL-10 and IL-18 in the cell culture supernatants in response to phytohaemagglutinin (PHA), Der p 1 and BLG were measured using the ELISA technique. After 3 years, symptoms of AD were obtained with a questionnaire completed by the parents. RESULTS: We observed significantly higher IL-13 levels in response to PHA in children who subsequently developed symptoms of AD (S: median, 291 pg/mL) compared with asymptomatic children (No-S: 149 pg/mL; P=0.021, Wilcoxon test). Similarly, in response to Der p 1 significantly higher IL-13 levels were observed in symptomatic children (S: 168.6; No-S: 61.6 pg/mL; P=0.0084). In response to BLG, IL-13 levels were 287.2 (S) and 123.6 pg/mL (No-S; P=0.19). No significant differences were found when comparing the IFN-gamma levels in CBMC cultures stimulated with PHA (S: 10.2; No-S: 17.6 IU/L; P=0.78), Der p 1 (S: 307.6; No-S: 616.2 IU/L; P=0.2) or BLG (S: 18; No-S: 28.5 IU/L; P=0.83; Fig. 2). The IL-18 and IL-10 levels and the stimulation index in response to IL-2, BLG and Der p 1 showed no significant difference between children who subsequently developed symptoms of AD and asymptomatic children. CONCLUSION: Our data suggest that enhanced IL-13 levels at birth are associated with the subsequent development of atopic symptoms at the age of 3 years.
Asunto(s)
Alérgenos/inmunología , Dermatitis Atópica/inmunología , Sangre Fetal/inmunología , Interleucina-13/biosíntesis , Leucocitos Mononucleares/inmunología , Antígenos Dermatofagoides/inmunología , Proteínas de Artrópodos , División Celular/inmunología , Células Cultivadas , Preescolar , Cisteína Endopeptidasas , Femenino , Humanos , Recién Nacido , Interferón gamma/biosíntesis , Masculino , Fitohemaglutininas/inmunología , Estudios ProspectivosRESUMEN
This paper reports the case of a 14-year-old child with Maroteaux-Lamy syndrome (mucopolysaccharidosis type 6) who was treated consecutively for compressive damage of the optic nerves, hydrocephalus communicans and progressive spastic tetraparesis within 2 years. The clinical course of the patient is presented and the pathophysiologic mechanisms of disease progression in patients with Maroteaux-Lamy syndrome are discussed and reviewed.
Asunto(s)
Mucopolisacaridosis VI/cirugía , Adolescente , Vértebras Cervicales/diagnóstico por imagen , Vértebras Cervicales/patología , Vértebras Cervicales/cirugía , Descompresión Quirúrgica , Femenino , Humanos , Hidrocefalia/diagnóstico , Hidrocefalia/etiología , Hidrocefalia/cirugía , Laminectomía , Imagen por Resonancia Magnética , Mucopolisacaridosis VI/complicaciones , Mucopolisacaridosis VI/diagnóstico , Atrofia Óptica/etiología , Atrofia Óptica/patología , Atrofia Óptica/cirugía , Paraparesia Espástica/diagnóstico , Paraparesia Espástica/etiología , Paraparesia Espástica/cirugía , Compresión de la Médula Espinal/etiología , Compresión de la Médula Espinal/cirugía , Síndrome , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Successful pregnancy is dependent upon T helper (Th)2-type-dominated immunological responsiveness in gestation-associated compartments. OBJECTIVE: In our study we observed the influence of the maternal Th2-associated cytokine pattern on the naive fetal T cell phenotype and asked if circulating Th2 cytokines of atopic mothers affects the Th1/Th2 differentiation of the fetus. METHODS: Cord blood mononuclear cells (CBMC) and peripheral blood mononuclear cells (PBMC) of the corresponding mothers were isolated. The proliferative response of CBMC and PBMC to Betalactoglobulin (BLG) was assessed by liquid scintillation counting. The cytokines interferon (IFN)-gamma, and interleukin (IL)-5, IL-10 and IL-13 in the cell culture supernatants were measured using the ELISA technique. We then defined two subgroups based on maternal levels of specific IgE against aeroallergens: sensitized mothers (MA(+)) and their neonates (NMA(+)) (n = 18) and non-sensitized mothers (MA(-)) and their neonates (NMA(-)) (n = 29). RESULTS: Nearly all mothers (98%) and neonates (92%) had a positive proliferation response after stimulation with BLG (mean stimulation index (10-90 percentile): neonates: 7 (2-15); mothers 14 (5-29)). In supernatants of BLG-stimulated cell cultures, sensitized mothers showed a significantly lower IFN-gamma concentration in comparison to non-sensitized mothers (MA(+) = 25; MA(-) = 123 IU/L; P < 0,05), whereas the neonates did not differ significantly (NMA(+) = 306; NMA(-) = 224 IU/L; n. s.). Nor was any difference found in the IL-13 concentration between the two groups of sensitized and non-sensitized mothers (MA(+) = 48; MA(-) = 125 pg/mL; n. s.). CBMC of neonates with a sensitized mother showed significantly higher IL-13 concentrations in response to BLG than neonates of non-sensitized mothers (NMA(+) = 1442, NMA(-) 738 pg/mL; P < 0.05). The IL-5 and IL-10 concentrations did not differ significantly within the neonatal and the maternal subgroups. CONCLUSIONS: Our data suggests that maternal sensitization to allergens is associated with the reduced maternal production of the Th2 antagonist IFN-gamma and elevated production of the Th2 cytokine IL-13 in the offspring.