RESUMEN
BACKGROUND: Anti-inflammatory therapy is a logical approach to slowing the inevitable lung function deterioration in cystic fibrosis (CF) patients. This study's aim was to evaluate inflammatory markers and disease progression in paediatric CF patients chronically treated with azithromycin or low-dose prednisolone. METHODS: The study included 204 patients with CF and 100 healthy controls; 102 CF patients were treated with basic therapy only (without anti-inflammatory treatment; WAT), and 102 individuals received basic therapy along with azithromycin (n = 59) or low-dose prednisolone (n = 43). The median duration of therapy was 24 months (range 12-82) with azithromycin and 31 months (range 12-180) with prednisolone. A cross-sectional analysis of plasma and sputum biomarkers was performed. RESULTS: Compared with the healthy controls, the WAT group showed elevated IFN-γ, IL-10 (total), and TGFß1 concentrations, and decreased TNFα (total) and adrenocorticotropic hormone (ACTH) levels (all p < 0.05). Plasma TNFα (total) concentrations in azithromycin/prednisolone patients were significantly higher than those in WAT patients and similar to those of healthy children. In contrast, IL-10 (total) levels were significantly decreased in azithromycin/prednisolone-treated patients compared with WAT patients. Children from the azithromycin group demonstrated ACTH levels similar to those of healthy controls. Azithromycin-treated patients showed a significantly reduced rate of CF-related liver disease and a significantly increased incidence of glucose metabolism disturbances. CONCLUSIONS: Steady-state anti-inflammatory treatments may have a sustained immunomodulatory action at systemic and local levels in CF patients. Further investigations are needed to assess the effects of supportive azithromycin therapy on the hypothalamic-pituitary-adrenal axis and the incidence of non-pulmonary CF complications.
Asunto(s)
Antibacterianos/uso terapéutico , Antiinflamatorios/uso terapéutico , Azitromicina/uso terapéutico , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/patología , Progresión de la Enfermedad , Prednisolona/uso terapéutico , Adolescente , Hormona Adrenocorticotrópica/sangre , Biomarcadores/sangre , Niño , Estudios Transversales , Fibrosis Quística/inmunología , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Femenino , Genotipo , Humanos , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Inflamación/patología , Interferón gamma/sangre , Interleucina-10/sangre , Elastasa de Leucocito/sangre , Masculino , Factor de Crecimiento Transformador alfa/sangre , Factor de Crecimiento Transformador beta/sangreRESUMEN
BACKGROUND: It is well known that the disease progression in cystic fibrosis (CF) patients may be diverse in subjects with identical mutation in CFTR gene. It is quite possible that such heterogeneity is associated with TNF-α and/or LT-α gene polymorphisms since their products play a key role in inflammation. The aim of the study was to investigate the possible roles of TNF gene polymorphisms in CF disease phenotype and progression. METHODS: 198 CF patients and 130 control subjects were genotyped for both TNF-α-308GA and LT-α + 252AG polymorphisms. RESULTS: The carriers of the TNF-α-308A allele more frequently had asthma as compared to patients homozygous for the TNF-α-308 G allele. In 9 of 108 (8.3%) of LTα + 252AA carriers, tuberculosis infection has been documented, whereas there was no case of tuberculosis among patients, either homozygous or heterozygous for LTα +252 G alleles (p = 0.01). We never observed virus hepatitis among LTα + 252GA carriers. The genotypes TNF-α-308GG - LT-α + 252AA and TNF-α-308GA - LT-α + 252AG were unfavorable with regard to liver disease development (both p < 0.05). It was also shown that neutrophil elastase activity was higher in sputum specimens from high TNF producers with genotypes TNF-α-308GA or LT-α + 252GG. In addition the carriers of such genotypes demonstrated a higher risk of osteoporosis development (p values were 0.011 and 0.017, respectively). CONCLUSIONS: The carriers of genotypes, which are associated with higher TNF-α production, demonstrated increased frequency of asthma, higher levels of neutrophil elastase, and decrease of bone density. On the contrary, the carriers of genotypes associated with low TNF-α production showed a higher frequency of tuberculosis infection.
Asunto(s)
Fibrosis Quística/genética , Polimorfismo Genético , Factor de Necrosis Tumoral alfa/genética , Alelos , Secuencia de Bases , Estudios de Casos y Controles , Niño , Fibrosis Quística/fisiopatología , Cartilla de ADN , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Osteoporosis/fisiopatología , Reacción en Cadena de la PolimerasaRESUMEN
60 children aged 1-2 years old (32 boys and 28 girls) were vaccinated with Priorix. Vaccinated children included healthy control (19 children, group 1), and children with immunological disturbances such as episodes of respiratory infection. From the latter group, 20 children did not receive (group 2), and 21 children received 0.15 mg/kg of Polyoxidonium simultaneously with the vaccine (group 3).On days 7 and 30 after vaccination, CD-markers on lymphocytes and concentration of specific antibodies, as well as levels of 11 cytokines in serum were evaluated by flow cytometry, ELISA, and multiplex techniques respectively. It was found that injection of Polyoxidonium skewed T helper differentiation to Th2 type. Antibody responses were significantly higher in children with preferable Th2 responses. Children from group 3 possessed higher titers of specific IgG-antibodies. Our study shows that Polyoxidonium could smooth out the immune reaction on vaccination. It is important for children with some immunological disturbances.
Asunto(s)
Adyuvantes Inmunológicos/farmacología , Anticuerpos Antivirales/biosíntesis , Citocinas/sangre , Vacuna contra el Sarampión-Parotiditis-Rubéola/inmunología , Piperazinas/farmacología , Polímeros/farmacología , Vacunación , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Preescolar , Femenino , Humanos , Lactante , Subgrupos Linfocitarios/efectos de los fármacos , Subgrupos Linfocitarios/inmunología , Masculino , Vacunas Atenuadas/inmunologíaRESUMEN
Surplus accumulation of regulatory T cells (Tregs) is known to be at the bottom of many morbid conditions, among them being neuropsychiatric diseases. In particular, Tregs may inhibit Th1 cells, including brain autoimmune lymphocytes, controlling the local microglial response and brain tissue homeostasis. The present study was undertaken in an attempt to suggest a novel approach for the treatment of maladaptation to mental stress associated with excessive Treg accumulation. Recently it was shown that alkylating drugs (ADs), such as melphalan and cyclophosphamide (Cy) in the dose 100-fold lower than cytostatic one are capable to disturb signal transduction by IL-2R. In this study we demonstrated that IL-2R is not a unique receptor, which may be blocked with ADs. Similar effect has been shown for two other surface receptors: TNFR and Fas. Molecular mechanisms of the receptor blockage were investigated on the model of TNF signaling. Study of NF-κB activity in nuclear extracts showed that alkylating agents act at the level of surface receptor or of the receptor platform. It was also shown that ADs administration in ultralow doses results in selective elimination of Tregs. In this study we used a new laboratory model of Treg accumulation in mice. Such Treg accumulation was associated with cognitive and behavioral abnormalities, which may be prevented by Cy administration.
Asunto(s)
Trastornos del Conocimiento/tratamiento farmacológico , Trastornos del Conocimiento/inmunología , Ciclofosfamida , Citocinas/inmunología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Estrés Psicológico/tratamiento farmacológico , Animales , Antineoplásicos Alquilantes/farmacología , Antineoplásicos Alquilantes/uso terapéutico , Conducta Animal/efectos de los fármacos , Ciclofosfamida/farmacología , Ciclofosfamida/uso terapéutico , Inmunosupresores/farmacología , Inmunosupresores/uso terapéutico , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Melfalán/farmacología , Melfalán/uso terapéutico , Ratones , Ratones Endogámicos BALB C , FN-kappa B/metabolismo , Receptores de Interleucina-2/inmunología , Estrés Psicológico/fisiopatología , Linfocitos T Reguladores/inmunologíaRESUMEN
Melphalan is an alkylating agent, which is commonly used as an antineoplastic drug. Its cytostatic effect can be realized in humans in the dose range of 0.6-1.4 mg/kg body weight. However, previously it was shown that in the case of gradual dose decrease, the number of targets for alkylation was also reduced and the drug lost its cytostatic properties switching to cell growth modifier. It has been postulated that application of alkylating agents in such ultra-low concentrations (50- to 100-fold lower than cytostatic ones) may result in a beneficial effect in the therapy of diseases associated with mucosa inflammation. The aim of the article was to investigate the effect of ultra-low doses of melphalan in the murine experimental colitis induced by the replacement of drinking water with 5% solution of dextran sulphate sodium (DSS). Daily administration of melphalan (25 microg/kg body weight) markedly reduced the severity of DSS-colitis as determined by clinical and quantitative histological criteria. Both systemic and local anti-inflammatory effects of melphalan have been observed. The possible mechanisms of the beneficial effect of the drug have been discussed.
Asunto(s)
Antineoplásicos Alquilantes/farmacología , Colitis/tratamiento farmacológico , Melfalán/farmacología , Transducción de Señal , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Antiinflamatorios/farmacología , Supervivencia Celular , Sulfato de Dextran/farmacología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Ratones Endogámicos BALB CRESUMEN
The aim of this study was to investigate measles-specific immunoglobulin G (IgG) subclass profile in vaccinated children and in adults with natural infection. Serum samples were collected before and 30 days after vaccination. The sera from 51 late convalescent adults and seven adults with natural measles infection at the 12th day after onset of rash have been also investigated. Measles IgG antibodies and specific IgG subclasses were tested by enzyme-linked immunosorbent techniques. In children younger than 3 years, the predominant subclass was IgG3, which contributed, on average, 63.3% of the total IgG response. The contributions of specific IgG1 and IgG4 to the total IgG antimeasles response were lower (19.9% and 16.8%, respectively), whereas IgG2 was not found. In contrast, in the group of children older than 4 years, just IgG2 was a predominant subclass; it contributed 42.6% of the total IgG response. Other subclasses were also present but the contribution was much lower. In adult volunteers with measles history, IgG2 was a predominant subclass of total IgG. Thus, in early convalescence IgG2 contributed 62% of the total IgG response, whereas in late convalescence the contribution was lower (41.4%). There were no visible differences in IgG subclass composition between subjects with natural infection and vaccinated children except those below 3 years of age. The humoral immune response of such subjects is immature and the IgG2 subclass of virus-specific antibodies has not been revealed in the sera.
Asunto(s)
Anticuerpos Antivirales/sangre , Formación de Anticuerpos/inmunología , Inmunoglobulina G/sangre , Vacuna Antisarampión/administración & dosificación , Virus del Sarampión/inmunología , Sarampión/sangre , Adulto , Anticuerpos Antivirales/inmunología , Niño , Preescolar , Femenino , Humanos , Inmunoglobulina G/inmunología , Lactante , Masculino , Sarampión/inmunología , Sarampión/prevención & control , Vacuna Antisarampión/inmunologíaRESUMEN
BACKGROUND AND AIM: Immunization with live virus vaccines may cause an immunosuppression with lymphopaenia, impaired cytokine production and defective lymphocyte response to mitogenes. These abnormalities were described in subjects vaccinated against measles. This study was performed to analyse the host immune response related to immunosuppression in subjects vaccinated with live attenuated rubella vaccine. METHODS: Eighteen schoolgirls, aged 11-13 years, were vaccinated with live attenuated rubella vaccine Rudivax. Before immunization, and 7 and 30 days after, peripheral blood was collected. Cellular fractions were subjected to flow cytometric analysis, and the lymphocyte response to phytohaemagglutinin was investigated. Plasma samples were analysed for cytokines (interleukin (IL)-4, IL-10, tumour necrosis factor-alpha, and interferon-gamma) by enzyme-linked immunosorbent assay techniques. RESULTS: On day 7 after vaccination, the number of each lymphocyte subset was decreased; however, only for CD3 and CD4 lymphocytes has a significant reduction been shown. On the contrary, tumour necrosis factor-alpha and IL-10 levels markedly increased and amounted to its maximum on day 30. Simultaneously, a significant reduction in plasma interferon-gamma and a profound decrease of the lymphocyte response to phytohaemagglutinin were shown. The changes were accompanied with marked elevation of plasma IL-4. CONCLUSIONS: Our data indicate that the vaccination with live attenuated rubella vaccine results in moderate but sustained immune disturbance. The signs of immunosuppression, including defective lymphocyte response to mitogene and impaired cytokine production, may persist for at least 1 month after vaccination.