RESUMEN
Immune system and bone marrow stromal cells play an important role in maintaining normal hematopoiesis. Lymphoid neoplasia disturbs not only development of immune cells, but other immune response mechanisms as well. Multipotent mesenchymal stromal cells (MSCs) of the bone marrow are involved in immune response regulation through both intercellular interactions and secretion of various cytokines. In hematological malignancies, the bone marrow stromal microenvironment, including MSCs, is altered. Aim of this study was to describe the differences of MSCs' immunological function in the patients with acute lymphoblastic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL). In ALL, malignant cells arise from the early precursor cells localized in bone marrow, while in DLBCL they arise from more differentiated B-cells. In this study, only the DLBCL patients without bone marrow involvement were included. Growth parameters, surface marker expression, genes of interest expression, and secretion pattern of bone marrow MSCs from the patients with ALL and DLBCL at the onset of the disease and in remission were studied. MSCs from the healthy donors of corresponding ages were used as controls. It has been shown that concentration of MSCs in the bone marrow of the patients with ALL is reduced at the onset of the disease and is restored upon reaching remission; in the patients with DLBCL this parameter does not change. Proliferative capacity of MSCs did not change in the patients with ALL; however, the cells of the DLBCL patients both at the onset and in remission proliferated significantly faster than those from the donors. Expression of the membrane surface markers and expression of the genes important for differentiation, immunological status maintenance, and cytokine secretion differed significantly in the MSCs of the patients from those of the healthy donors and depended on nosology of the disease. Secretomes of the MSCs varied greatly; a number of proteins associated with immune response regulation, differentiation, and maintenance of hematopoietic stem cells were depleted in the secretomes of the cells from the patients. Lymphoid neoplasia leads to dramatic changes in the functional immunological status of MSCs.
Asunto(s)
Linfoma de Células B Grandes Difuso , Células Madre Mesenquimatosas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Linfoma de Células B Grandes Difuso/inmunología , Linfoma de Células B Grandes Difuso/patología , Linfoma de Células B Grandes Difuso/metabolismo , Masculino , Adulto , Femenino , Persona de Mediana Edad , Células de la Médula Ósea/inmunología , Proliferación Celular , Adulto JovenRESUMEN
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
BACKGROUND AND AIM: Chronic infection with Pseudomonas aeruginosa in patients with cystic fibrosis (CF) causes progressive deterioration in lung function. The purpose of this trial was to assess the efficacy and tolerability of a tobramycin highly concentrated solution for inhalation (TSI) [300mg/4mL; Bramitob when added to other antipseudomonal therapies in CF patients with chronic P. aeruginosa infection. METHODS: In a multinational, double-blind, multicenter study, CF patients with chronic P. aeruginosa infection were randomized to receive nebulized tobramycin or placebo over a 24-week study period in which 4-week treatment periods ('on' cycles) were followed by 4-week periods without treatment ('off' cycles). Forced expiratory volume in 1 second (FEV(1)) percentage of predicted normal was used as the primary efficacy outcome parameter. Forced vital capacity (FVC), forced expiratory flow at 25-75% of FVC (FEF(25)(-)(75%)), P. aeruginosa susceptibility, minimum concentration required to inhibit 90% of strains (MIC(90)), rates of P. aeruginosa-negative culture, P. aeruginosa persistence and superinfection, need for hospitalization and parenteral antipseudomonal antibiotics, loss of school/working days due to the disease, and nutritional status (bodyweight and body mass index) were considered as secondary efficacy outcome parameters. Adverse events reporting, audiometry, and renal function were monitored to evaluate the tolerability and safety of TSI. RESULTS: A total of 247 patients were randomized in the study. At endpoint time assessment (week 20), FEV(1) was significantly increased in the tobramycin group and the adjusted mean difference between groups (intention-to-treat population) was statistically significant (p < 0.001). At the same time, clinically relevant improvements in FVC and FEF(25-75%) were detected in the TSI group (p = 0.022 and p = 0.001, respectively). The microbiologic outcomes at the end of the last 'on' cycle period were significantly better in the TSI group than the placebo group (p = 0.024), although there was a concomitant trend toward an increase in the MIC of isolated P. aeruginosa strains. The percentage of patients hospitalized as well as the need for parenteral antipseudomonal antibiotics was significantly lower in the TSI group (p = 0.002 and p = 0.009, respectively). Patients treated with TSI had fewer lost school/working days due to the disease (p < 0.001). A favorable effect of tobramycin in terms of an increase in bodyweight and body mass index was also noted, when compared with placebo, at all time points (p < 0.01 and p < 0.001, respectively). No significant changes in serum creatinine and auditory function were detected. The proportion of patients with drug-related adverse events was 15% in both treatment groups. CONCLUSIONS: Long-term, intermittent administration of this aerosolized tobramycin formulation (300mg/4mL) in CF patients with P. aeruginosa chronic infection significantly improved pulmonary function and microbiologic outcome, decreased hospitalizations, increased nutritional status, and was well tolerated.
Asunto(s)
Antibacterianos/uso terapéutico , Fibrosis Quística/tratamiento farmacológico , Infecciones por Pseudomonas/tratamiento farmacológico , Tobramicina/uso terapéutico , Administración por Inhalación , Adolescente , Adulto , Aerosoles , Antibacterianos/administración & dosificación , Antibacterianos/efectos adversos , Niño , Enfermedad Crónica , Fibrosis Quística/complicaciones , Femenino , Humanos , Masculino , Persona de Mediana Edad , Infecciones por Pseudomonas/complicaciones , Pseudomonas aeruginosa , Tobramicina/administración & dosificación , Tobramicina/efectos adversos , Resultado del TratamientoRESUMEN
BACKGROUND AND AIM: Macrolide antibiotics are widely used in the treatment of suppurative lung diseases including cystic fibrosis (CF), the most common inherited fatal disease in the Caucasian population. This condition is characterized by secondary Pseudomonas infection resulting in neutrophil infiltration within the airways. The aim of the study was to investigate the evolution of inflammatory process in CF patients receiving long-term clarithromycin therapy. METHODS: Twenty-seven CF patients (mean age, 12 years) were enrolled into the study. Beside the basic therapy the patients were treated with clarithromycin at a dose of 250 mg every other day orally. All patients were routinely examined every 3 months. Blood and sputum were collected before clarithromycin treatment and then again 3, 6 and 12 months after the drug prescription. Cytokine concentrations (tumor necrosis factor-alpha, interleukin-8, interleukin-4, interferon-gamma) in the sputum and plasma were assayed. Peripheral blood lymphocyte response to phytohemagglutinin was also evaluated. RESULTS: Clarithromycin treatment resulted in a marked reduction of the cytokine levels both in the sputum and plasma specimens. At the same time, the interferon-gamma/interleukin-4 ratio has been significantly elevated. In addition, a sustained increase of peripheral blood lymphocyte response to phytohemagglutinin was demonstrated. These changes were associated with a significant improvement of the lung function. CONCLUSIONS: The beneficial effect of the prolonged treatment of CF patients with a 14-membered ring macrolide antibiotic clarithromycin seems to be associated not only with down-regulation of the inflammatory response, but also with immunological changes including the switch from Th2 to Th1 type response.
Asunto(s)
Antibacterianos/uso terapéutico , Antiinflamatorios no Esteroideos/uso terapéutico , Claritromicina/uso terapéutico , Fibrosis Quística/tratamiento farmacológico , Factores Inmunológicos/uso terapéutico , Adolescente , Animales , Niño , Fibrosis Quística/sangre , Fibrosis Quística/inmunología , Citocinas/sangre , Femenino , Humanos , Inflamación , Linfocitos/inmunología , Masculino , Pruebas de Función Respiratoria , Esputo/químicaRESUMEN
BACKGROUND: Fecal elastase-1 (E1) test is a sensitive and specific indirect test. However, there are few data on the best cut-off level in the assessment of exocrine pancreatic function in cystic fibrosis (CF). MATERIAL AND METHODS: In 725 CF patients and 243 healthy subjects (HS) from Greece, Russia, Poland and the United Kingdom, E1 concentrations were measured. The best cut-off levels for the discrimination between CF and HS (for whole group as well as for individual countries) were calculated. RESULTS: The best cut-off level for the differentiation between CF pancreatic insufficiency and normal pancreatic function in HS was found to be 184 microg/g of feces. However, some inter-country differences were stated. E1 concentrations in the UK subgroup were significantly lower than those found in Polish and Russian CF patients. E1 concentrations in Greek patients were significantly higher than in the other countries. However, E1 concentrations in Delta F508 homozygotes were very similar in all studied subgroups. IN CONCLUSION: In clinical practice, instead of a single best cut-off level for the E1 test, we suggest using a range of values (160-200 microg/g). The presence of different best cut-off levels within countries is a practical consequence of the different distribution of pancreatic function.