Immunomodulatory effect of IL-2 induced bone marrow mononuclear cell therapy on control of allergic asthma

Asthma is a chronic airway disease. Allergic reactions and T helper (h)2 immune response play a key role in asthma occurrence. Cell therapy can control inflammation and remodeling responses in allergic asthma, and cytokines can change this effect. Therefore, in this study, the effect of treated cell therapy with IL-2 to control allergic asthma was studied. Bone marrow cells were extracted and co-cultured with IL-2 and the cells were used via intra-tracheal administration in allergic asthma mice. Levels of IL-4, IL-5, IL-13, Leukotriene B4 and C4, and remodeling factors were measured. At least, a histopathology test of lung tissue was done. Type2 cytokines, leukotrienes, remodeling factors, mucus secretion, goblet cell hyperplasia, peri-bronchial and peri-vascular inflammation were significantly (p˂0.05) decreased by treating with bone marrow-derived mononuclear cells (BMDMCs) and IL-2-BMDMCs. Treatment with IL-2-BMDMCs could significantly decrease IL-13, transforming growth factor (TGF)-β, HP levels, and mucus secretion (p˂0.05) compared to BMDMCs treatment. In this study, BMDMCs and IL-2-BMDMCs therapy could decrease inflammation, allergic, and remodeling factors in allergic asthma. Cell therapy with BMDMCs had a strong and notable effect on the control of allergic asthma pathophysiology when co-cultured and used with IL-2 (AU)

Hypoxia-mediated down-regulation of miRNAs’ biogenesis promotes tumor immune escape in bladder cancer

Background The study examines the function of hypoxia-mediated down-regulation of microRNAs (miRNAs) (mir-30c, mir-135a, and mir-27a) in the process of bladder cancer immune escape. Methods Quantitative Real-time PCR (qRT-PCR) was carried out to determine gene expression levels of Drosha and Dicer under hypoxia treatment, while western blotting and flow cytometry were used to determine protein expression. Seven reported miRNAs were identified via qRT-PCR assay. Flow cytometry detection of CD3/CD4/CD8-positive expression and statistics. Enzyme-linked immunosorbent assay (ELISA) detected cellular immune factors content. Cell apoptosis was checked via flow cytometry assay. Luciferase report assay and western blot assays were both used to verify the relationship between miRNAs and Casitas B-lineage lymphoma proto-oncogene b (Cbl-b). The animal model was established and Hematoxylin–eosin (HE) staining, TdT-mediated dUTP Nick-End Labeling (TUNEL) staining, and immunohistochemistry (IHC) assays were separately used to verify the conclusions. Results The CD3 + /CD4 + expression was increased in the hypoxia group, while CD3 + /CD8 + expression, the cellular immune factors content Interleukin-2 (IL-2) and Tumor Necrosis Factor-α (TNFα) along with the cell apoptosis were suppressed. The protein expression of Cbl-b was found to be up-regulated in the hypoxia group. After constructing the overexpression/ knockdown of Cbl-b in peripheral blood mononuclear cell (PBMC), Cbl-b has been found to promote tumor immune escape in bladder cancer. Furthermore, Cbl-b had been identified as the co-targets of mir-30c, mir-135a, and mir-27a and down-regulation of miRNA biogenesis promotes Cbl-b expression and deactivating T cells in vitro/in vivo. Conclusion Hypoxia-mediated down-regulation of miRNAs’ biogenesis promotes tumor immune escape in bladder cancer, which could bring much more advance to the medical research on tumors (AU)

¿Pueden ser la interleucina-2 y la interleucina-1ß biomarcadores específicos de la sintomatología negativa en la esquizofrenia? / Can interleukin-2 and interleukin-1ß be specific biomarkers of negative symptoms in schizophrenia?

Introducción: Hay evidencias que sugieren la existencia de alteraciones de algunas citocinas en pacientes con esquizofrenia, pero su asociación con la psicopatología aún no está clara. El objetivo de este estudio es determinar si los niveles de citocinas proinflamatorias (factor de necrosis tumoral-alfa, interleucina [IL]-6, IL-2, IL-1ß, IL-1RA) están aumentados en pacientes ambulatorios clínicamente estables en comparación con individuos sanos, y analizar si podrían ser biomarcadores específicos de las diferentes dimensiones clínicas de la esquizofrenia. Métodos: Se evaluaron 73 pacientes con esquizofrenia en sus primeros 10 años de evolución de la enfermedad y 73 controles sanos pareados por edad y sexo. Se realizó una evaluación precisa de las dimensiones clínicas (positiva, negativa, depresiva y cognitiva) en estos pacientes. Resultados: Solo los niveles de IL-6 están significativamente elevados en los pacientes tras controlar por índice de masa corporal, perímetro abdominal, tabaquismo y tratamiento psicofarmacológico en comparación con sus controles sanos. Tras ajustar por varios factores de confusión, los modelos de regresión lineal múltiple identificaron cómo las concentraciones de IL-1ß predicen los síntomas negativos, psicopatología general y gravedad global de la Escala del Síndrome Positivo y Negativo, mientras los niveles de IL-2 predicen el dominio motivación y placer de la Entrevista de Evaluación Clínica para Síntomas Negativos y la puntuación global en la Escala de Funcionamiento Personal y Social. Sin embargo, el rendimiento cognitivo, la gravedad de los síntomas depresivos y positivos no correlacionaron con ninguna de las citocinas. Conclusiones: Nuestros hallazgos sugieren que las concentraciones de IL-6 permanecen elevadas en pacientes estables con esquizofrenia. Mientras que la IL-2 marca específicamente la gravedad en el dominio motivación y placer de la sintomatología negativa, la IL-1ß no es específica para esta dimensión, ya que también predice la gravedad de la sintomatología general y global

Introduction: Evidence suggests the existence of cytokine disturbances in patients with schizophrenia but their association with psychopathology is still unclear. The aim of the current study was to determine if pro-inflammatory cytokine levels (tumor necrosis factor-alfa, interleukin (IL)-6, IL-2, IL-1ß, IL-1RA) are increased in stable outpatients compared with healthy subjects, and to analyze if they could be specific biomarkers of clinical dimensions in schizophrenia. Methods: We studied 73 stable outpatients with schizophrenia in their first 10 years of illness and 73 age- and sex-matched healthy controls. An accurate assessment of clinical dimensions (positive, negative, depressive, cognitive) was performed in patients. Results: Only IL-6 levels were significantly increased in patients after controlling for body mass index, waist circumference, smoking, and psychopharmacological treatment, compared with healthy subjects. After adjusting for several confounders, multiple linear regression models identified that Positive and Negative Syndrome Scale negative symptoms, general psychopathology, and global severity are predicted by IL-1ß concentrations, while motivation and pleasure domain of Clinical Assessment Interview for Negative Symptoms and Personal and Social Performance global functioning scores are predicted by IL-2 levels. Cognitive performance, positive, and depressive symptom severity did not correlate with any cytokine. Conclusions: Our findings suggested that IL-6 concentrations are elevated in stable patients with schizophrenia. Whereas IL-2 specifically marks severity of the motivation and pleasure domain of negative symptoms, IL-1ß is not specific to this dimension as it also predicts severity of general and global symptomatology

Single nucleotide polymorphisms of IL-2, but not IL-12 and IFN-y, are associated with increased susceptibility to chronic spontaneous urticaria

Background: A clear picture of interaction of Th1/Th2 cytokines in pathogenesis of chronic spontaneous urticaria (CSU), remains elusive. Impaired IFN-γ production and decreased levels of IL-2 have been reported. The aim of this study was to evaluate the association of Th1 cytokines; IL-2, IL-12 and IFN-γ polymorphisms with CSU. Methods: 90 patients with CSU and 140 age-sex matched subjects were included in this study. DNA samples were evaluated through PCR-SSP assay in order to detect single nucleotide polymorphisms of IL-12 (A/C -1188) or (rs3212227), IFN-γ (A/T UTR5644) or (rs2069717) and IL-2 (G/T -330 and G/T +166) or (rs2069762 and rs2069763). Results: G allele at -330 at promoter region of IL-2 gene was overrepresented in CSU. Heterozygotes (GT) at this locus and heterozygotes at +166 of IL-2 gene (GT) were more prevalent in CSU group. Additionally, the haplotype GT for loci -330 and +166 of IL-2 gene was powerfully associated with CSU (OR (95%CI) = 57.29 (8.43-112.7)). Conclusions: SNP at position -330 and +166 of IL-2 gene are differently expressed in CSU. The haplotype GT of IL-2 at -330 and +166 might confer vulnerability to a number of immunological disorders in Iranian region (AU)

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Association of interleukin-2 and interferon-γ single nucleotide polymorphisms with Juvenile systemic lupus erythematosus

Purpose: Juvenile systemic lupus erythematosus (JSLE) is a severe and chronic autoimmune disease of unknown origin. Inflammatory cytokines can play a pivotal role in the pathogenesis of JSLE, while their secretion is under genetic control. The current investigation was performed to analyse the associations of particular single nucleotide polymorphisms (SNPs) of interleukin-2 (IL-2) and interferon-gamma (IFN-γ) genes in a case control study. Materials and methods: The allele, genotype and haplotype frequencies of the polymorphic IL-2 (G/T at −330, rs2069762, and G/T at +166, rs2069763) and IFN-γ (A/T at +874, rs2430561) genes were estimated in 59 patients with JSLE by contrast with 140 healthy controls using polymerase chain reaction with sequence-specific primers method. Results: Results of the analysed data revealed a negative allelic association for JSLE in IL-2 −330/T (P=0.02), as well as a positive allelic association for IL-2 −330/G (P=0.02). IL-2 GG genotype (−330) in the patient group was also significantly overrepresented (P<0.001), while IL-2 GT genotype (−330) was notably decreased in the patients with JSLE (P<0.001). Additionally, the frequency of IL-2 (−330, +166) GT haplotype was significantly higher in the patient group (P<0.001). Conclusion: IL-2 cytokine gene polymorphisms could affect individual susceptibility to JSLE and can take on the role of possible genetic markers for vulnerability to JSLE

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Association of Interleukin-2, but not Interferon-Gamma, single nucleotide polymorphisms with juvenile idiopathic arthritis

BACKGROUND: Cytokines, including interleukin-2 (IL-2) and interferon-gamma (IFN-γ), seem to play a role in the pathogenesis of juvenile idiopathic arthritis (JIA). The aim of this study was to investigate the associations of IL-2 and IFN-γ single nucleotide polymorphisms (SNPs) with susceptibility to JIA in an Iranian population. METHODS: enomic DNA of 54 Iranian patients with JIA and 139 healthy unrelated controls were typed for IL-2 (G/T at −330 and +166) as well as IFN-γ gene (A/T at +874), using polymerase chain reaction with sequence-specific primers method, and compared between patients and controls. RESULTS: A significantly higher frequency of the IL-2 −330 GG genotype (p < 0.01) was found in the JIA patients compared to the controls. However, the GT genotype at the same position was notably lower than in controls (p < 0.01). Moreover, IL-2 (−330, +166) GT haplotype was more frequent in patients with JIA in comparison with controls. No significant differences was observed between the two groups of case and control for IL-2 (G/T at +166) and IFN-γ (A/T at +874) SNPs. CONCLUSION: The results of the current study suggest that certain SNPs of IL-2 gene have association with individuals' susceptibility to JIA. However, further investigations are required to confirm the results of this study

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Improving T-cell assays for diagnosis of latent TB infection: Confirmation of the potential role of testing Interleukin-2 release in Iranian patients

BACKGROUND: Since gamma interferon release assays (IGRAs) cannot differentiate between active tuberculosis and latent tuberculosis infection (LTBI), development of rapid and specific diagnosis tools are essential for discriminating between active tuberculosis (TB) from LTBI. Both IGRAs are based on Mycobacterium tuberculosis-specific antigens, namely, early secretory antigenic target 6 (ESAT-6) and 10kDa culture filtrate (CFP-10). The aim of this study was to evaluate the potential value of IL-2 secretion by whole blood cells after stimulation with rESAT-6 and rCFP-10 for discriminating between active and latent tuberculosis. METHODS: Interleukin-2 and IFN-γ were measured after blood stimulation of 90 cases (30 with active TB, 30 with LTBI and 30 healthy controls) with recombinant ESAT-6 and CFP-10. Receiver operating characteristic (ROC) curve analysis was conducted to determine the best IL-2 and IFN-γ result thresholds in discriminating between cases with active or latent TB, and the corresponding sensitivity and specificity were recorded. RESULTS: The IFN-γ release assay demonstrated a good sensitivity and specificity (sensitivity 83-84% and specificity 92%) for diagnosis of tuberculosis. The discrimination performance of IL-2 assay (assessed by the area under ROC curve) between LTBI and patients with active TB were 0.75 and 0.8 following stimulation with rESAT-6 and rCFP-10, respectively. Maximum discrimination was reached at a cut-off of 11.6pg/mL for IL-2 after stimulation with recombinant rESAT-6 with 72% sensitivity and 79% specificity and 10.7pg/mL for IL-2 following stimulation with rCFP-10 with 75% sensitivity and 79% specificity, respectively. CONCLUSION: This study demonstrates that rESAT-6 and rCFP-10 can provide a sensitive and specific diagnosis of TB. In addition, it was shown that IL-2 may be serving as a marker for discriminating LTBI and active TB

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The impact of the IL-1B, IL-1Ra, IL-2, IL-6 and IL-10 gene polymorphisms on the development of Behcet's disease and their association with the phenotype / Impacto de los polimorfismos genéticos de IL-1 beta, IL-1Ra, IL-2, IL-6 e IL-10 en el desarrollo de la enfermedad de Behcet y su asociación con el fenotipo

Background and objective: This trial was designed to investigate the effects of the interleukin (IL)-1β, IL-1Ra, IL-2, IL-6, IL-10 gene polymorphisms on Behcet's disease (BD) occurrence and the association between the polymorphisms and the phenotype. Materials and method: The study population consisted of 71 patients and 70 age and gender-matched healthy subjects. Each of the participants had 2cc of blood withdrawn, which was placed into a whole blood tube, and the DNA was obtained using the NucleoSpin® Blood DNA Isolation kit. To display the band lengths, the products were amplified using the primary pairs of the interleukins investigated and developed in a 2% agarose gel. Results: There were no significant differences between the groups with respect to the IL-1Ra, IL-1β, IL-2, IL-6 and the IL-10 gene polymorphism distributions. In the patient group the IL-1RN2 gene polymorphism was detected to be statistically correlated with the presence of articular involvement (p = 0.0283) and the IL-1β gene polymorphism was statistically correlated with the presence of an ocular lesion (p = 0.0178). The evaluation of the IL-2 gene polymorphism (p = 0.0065) and IL-10 gene polymorphism (p = 0.0483) distributions with respect to age of BD onset revealed a statistically significant distribution. Conclusion: The statistical correlations between the articular involvement and IL-1RN, the ocular involvement and the IL-1β, and the age of disease onset and the IL-2 and IL-10 gene polymorphisms, detected for the first time in the literature, suggest that these polymorphisms could be statistically associated with the disease symptoms and used as prognostic factors (AU)

Fundamento y objetivo: Este estudio fue designado para investigar los efectos de los polimorfismos genéticos de interleucina (IL)-1β, IL-1Ra, IL-2, IL-6 e IL-10 en la ocurrencia de la enfermedad de Behcet (EB) y la asociación entre los polimorfismos y el fenotipo. Materials y método: La población de estudio consistió en 71 pacientes y 70 sujetos sanos emparejados por edad y sexo. A cada participante se le extrajeron 2cc de sangre y el ADN se obtuvo usando el kit NucleoSpin® Blood DNA Isolation. Para mostrar las longitudes de las bandas, los productos fueron amplificados usando los primeros pares de las IL investigadas y se desarrollaron en un gel de agarosa al 2%. Resultados: No hubo diferencias significativas entre los grupos en relación con las distribuciones de los polimorfismos genéticos de IL-1Ra, IL-1β, IL-2, IL-6 e IL-10. En el grupo de pacientes, el polimorfismo genético de IL-1RN2 detectado se correlacionó estadísticamente con la presencia de afección articular (p = 0,0283), y el polimorfismo genético de IL-1β se correlacionó estadísticamente con la presencia de lesión ocular (p = 0,0178). La evaluación de la distribución del polimorfismo genético de IL-2 (p = 0,0065) e IL-10 (p = 0,0483) en relación con la edad de inicio de la EB reveló una distribución estadísticamente significativa. Conclusión: La correlación estadística entre afección articular e IL-1RN, afección ocular e IL-1β, y la edad de inicio de la enfermedad y los polimorfismos genéticos de IL-2 e IL-10, detectados por primera vez en la literatura médica, evidencian que estos polimorfismos se asociaron estadísticamente a los síntomas de la enfermedad y se podrían usar como factores pronósticos (AU)

Relación entre la expresión de IL-2 e IL-4 y sus polimorfismos y los riesgos de padecer infección por Mycoplasma pneumoniae y asma en niños / Associations of IL-2 and IL-4 Expression and Polymorphisms With the Risks of Mycoplasma pneumoniae Infection and Asthma in Children

Introducción: El asma es una afección inflamatoria de las vías respiratorias. Las infecciones porMycoplasma pneumoniae pueden exacerbar los síntomas del asma. Se ha demostrado que la interleucina2 y la interleucina4 participan en las reacciones inmunitarias e inflamatorias. Hemos estudiado la relación entre los polimorfismos de la IL2 y la IL4 y su expresión y el riesgo de padecer asma e infección por M.pneumoniae en niños. Métodos: Se reclutó a 392 niños asmáticos y 849 controles para el estudio. Se genotiparon 8 polimorfismos en IL2 e IL4 con la plataforma MassARRAY de Sequenom. La infección por M.pneumoniae y el número de copias se establecieron mediante PCR fluorescente. Los niveles séricos de expresión de IL-2 e IL-4 se midieron con ELISA. Resultados: Hallamos una relación significativa entre el polimorfismo rs6534349 de IL2 y el aumento de riesgo de sufrir asma (heterocigóticos, p = 0,029; variantes homocigóticas, p = 0,013), así como entre el polimorfismo rs2227284 de IL4 y una reducción del riesgo de padecer asma (heterocigóticos, p = 0,026; variantes homocigóticas, p = 0,001). Además, la relación con otros polimorfismos, excepto el rs2070874, se hizo evidente al agrupar a los niños asmáticos según la clasificación GINA de control y gravedad del asma. Asimismo, los niveles séricos de expresión de IL-2 e IL-4 fueron significativamente mayores en los sujetos no infectados (p = 0,038) e infectados (p = 0,011) por M.pneumoniae, respectivamente. Esta observación también se cumple entre los pacientes asmáticos (p = 0,016 para IL-2 y p = 0,042 para IL-4), pero en los controles no asmáticos solo se cumple en el caso de la IL-4 (p = 0,032). Del mismo modo, observamos que el genotipo GG rs6534349 estaba claramente relacionado con un aumento de las posibilidades de tener una infección con alta carga de M.pneumoniae (p = 0,0376). Conclusiones: La IL2 y la IL4 podrían ser biomarcadores importantes para calcular el riesgo de padecer asma, así como infección por M.pneumoniae, en niños

Introduction: Asthma is an inflammatory disorder of the airways and the symptoms of asthma could be exacerbated by Mycoplasma pneumoniae infection. Interleukin-2 and interleukin-4 have been implicated in immune and inflammatory reactions. We examined the associations of IL2 andIL4 polymorphisms and expression with the risks of asthma and M. pneumoniae infection in children. Methods: 392 asthmatic children and 849 controls were recruited into the study. Eight polymorphisms inIL2 and IL4 were genotyped with Sequenom MassARRAY platform. M. pneumoniae infection and copy number was determined with fluorescence PCR. IL-2 and IL-4 serum expression levels were determined by using ELISA. Results: We found a significant association of IL2 rs6534349 polymorphism with increased asthma risk (heterozygotes, P = .029; homozygous variants; P = .013) and of IL4 rs2227284 polymorphism with reduced asthma risk (heterozygotes, P = .026; homozygous variants; P = .001). Besides, the association of other polymorphisms, except rs2070874 polymorphism, became apparent when the asthmatic children were grouped according to GINA classification of asthma control and severity. In addition, IL-2 and IL-4 serum expression levels were significantly higher in M. pneumoniae negative (P = .038) and positive (P = .011) subjects respectively. This observation holds true among asthmatic patients (P = .016 for IL-2 and P = .042 for IL-4), but only the IL-4 observation remained correct among non-asthmatic controls (P = .032). We also observed that the rs6534349 GG genotype was significantly associated with increased odds of getting high load M. pneumoniae infection (P = .0376). Conclusions: IL2 and IL4 could be important biomarkers for estimating the risks of asthma and M. pneumoniae infection in children

Evaluation of serum levels of IL-6, TNF-alpha, IL-10, IL-2 and IL-4 in patients with chronic hepatitis

BACKGROUND: Changes in various cytokine activities have been reported during both HBV and HCV infections, while an imbalance of pro-inflammatory and anti-inflammatory cytokine production influences their immunopathogenesis. The aims of the present study are (a) to measure serum levels of interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), interleukin-10 (IL-10), interleukin-2 (IL-2) and interleukin-4 (IL-4) in a sample of patients affected either by chronic HBV infection or by chronic HCV infection and in healthy controls (b) to correlate serum levels of IL-6, TNF-α, IL-10, IL-2 and IL-4 with biochemical markers of liver disease and (c) to evaluate differences of the aforementioned cytokines between HBV and HCV patients, as well as between patients and healthy controls. METHODS: The study population consisted of 50 patients with chronic hepatitis B, 40 patients with chronic hepatitis C and 30 healthy controls aged between 28 and 75 years. Biochemical markers of liver disease were evaluated by routine methods approved by IFCC. Serum concentrations of IL-6, TNF-α, IL-10, IL-2 and IL-4 were determined with the Human Cytokine/Chemokine Panel I Merck Millipore. RESULTS: HBV patients showed statistically significant difference in TNF-α and IL-2 levels, versus healthy controls. HCV patients showed statistically significant difference in TNF-α, IL-10 and IL-2 levels versus healthy controls. IL10 and IL-2 levels were significantly different between HBV and HCV patients. CONCLUSIONS: This study evaluated the serum cytokine levels (IL-6, TNF-α, IL-10, IL-2 and IL-4) of chronic hepatitis B or C patients, as well as the differences in such levels between patients and healthy controls. Correlations of cytokine levels with biochemical markers of liver disease were also observed, reflecting the degree of activity of the inflammatory process in the liver

ANTECEDENTES: Tanto en las infecciones por VHB como por VHC se han notificado cambios en las diversas actividades de las citocinas, y es conocido que su inmunopatogénesis está influida por un desequilibrio en la producción de citocinas pro y antiinflamatorias. Los objetivos del presente estudio son: a) medir las concentraciones séricas de interleucina 6 (IL-6), factor de necrosis tumoral α (TNF-α), interleucina 10 (IL-10), interleucina 2 (IL-2) e interleucina 4 (IL-4) en una muestra de pacientes afectados, ya sea por una infección crónica por VHB o por VHC y en controles sanos; b) correlacionar las concentraciones séricas de IL-6, TNF-α, IL-10, IL-2 e IL-4 con los marcadores bioquímicos de enfermedad hepática, y c) evaluar las diferencias de las citocinas antes mencionadas entre los pacientes con VHB y con HCV, así como entre los pacientes y los controles sanos. MÉTODOS: La población del estudio consistió en 50 pacientes con hepatitis B crónica, 40 pacientes con hepatitis C crónica y 30 controles sanos de edades comprendidas entre 28 y 75 años. Se evaluaron los marcadores bioquímicos de la enfermedad hepática mediante métodos rutinarios aprobados por la IFCC. Las concentraciones séricas de IL-6, TNF-α, IL-10, IL-2 e IL-4 se determinaron mediante el Panel I de citocinas/quimiocinas humanas de Merck Millipore. RESULTADOS: Los pacientes con VHB mostraron diferencias estadísticamente significativas en las concentraciones de TNF-α e IL-2, comparadas con las de controles sanos. Los pacientes con HCV mostraron diferencias estadísticamente significativas en TNF-α, IL-10 e IL-2 respecto a las concentraciones de los controles sanos. Las concentraciones de IL-10 e IL-2 fueron significativamente diferentes entre los pacientes con VHB y con HCV. CONCLUSIONES: Este estudio evaluó las concentraciones séricas de citocinas (IL-6, TNF-α, IL-10, IL-2 e IL-4) de pacientes con hepatitis crónica B o C, así como las diferencias en dichas concentraciones entre pacientes y controles sanos. También se observaron correlaciones de las concentraciones de citocinas con marcadores bioquímicos de la enfermedad hepática, lo que refleja el grado de actividad del proceso inflamatorio en el hígado

Propuesta biotecnológica para el tratamiento del cáncer de cérvix uterino, empleando liposomas / Biotechnological proposal for cervical cancer treatment using liposomes

Los nanotransportadores de fármacos son una excelente opción para formar sistemas farmacéuticos eficientes y seguros. Interleucina 2 (IL-2) es eficaz en la terapia antitumoral, sin embargo su administración sistémica se ha limitado por su alta toxicidad. En el presente trabajo se aborda la investigación en animales del tratamiento antitumoral con IL-2 transportada en liposomas frente a IL-2 libre, y se aborda un paso imprescindible para el futuro uso de los liposomas con IL-2 como terapia biotecnológica para pacientes con carcinoma de cérvix: los primeros estudios de estabilidad farmacéutica

Drug nanosystems are an excellent option to form efficient and safe pharmaceutical systems. Our team has developed methodology based on the use of Interleukin 2 (IL-2) which has proven very effective in antitumor therapy, but systemic administration is limited by its high toxicity. The present work discusses in vivo evaluation of the tumor using IL-2 carried in liposomes against IL-2 free, and also addresses an important and necessary step for the future use of IL-2 liposomes in biotechnology therapy for patients with carcinoma of the cervix: the early pharmaceutical stability studies

Concentraciones de interleucina-2 en preeclámpticas y embarazadas normotensas sanas / Interleukin-2 concentrations in preeclamptic and healthy normotensive pregnant patients

Objetivo Comparar las concentraciones de IL-2 en pacientes con preeclampsia y embarazadas normotensas sanas. Material y métodos Se seleccionó un total de 100 pacientes. Se incluyeron a 50 pacientes preeclámpticas como los casos (grupo A) y un grupo control que fue seleccionado por tener una edad y un índice de masa corporal similares al grupo de estudio, y consistió en 50 embarazadas sanas (grupo B). Las muestras de sangre para la determinación de IL-2 se recolectaron en todas las pacientes antes del parto e inmediatamente después del diagnóstico en el grupo de casos. Resultados No se encontraron diferencias significativas con relación a la edad materna, edad gestacional e índice de masa corporal al momento de la toma de la muestra (p=ns). Se observaron diferencias estadísticamente significativas entre los grupos en los valores promedio de presión arterial sistólica y diastólica (p<0,05). Tampoco se encontraron diferencias estadísticamente significativa en las concentraciones de IL-2 entre las pacientes en el grupo de estudio (68,7±29,6pg/ml) y las pacientes del grupo control (59,9±18,4pg/ml; p=ns), pero si se observó una correlación débil, positiva y significativa con los valores de presión arterial sistólica (r=0,227; p<0,05).Conclusiones Las preeclámpticas presentaron concentraciones similares de IL-2 al compararlo con embarazadas normotensas sanas (AU)

Objective To compare interleukin-2 concentrations in patients with preeclampsia and healthy normotensive pregnant women. Material And Methods One hundred patients were selected. Fifty preeclamptic patients were selected as cases (group A) and 50 healthy pregnant women with a similar age and body mass index to patients in group A were selected as controls (group B). Blood samples for interleukin-2 determination were collected in all patients before labor and immediately after diagnosis in the study group. Results There were no significant differences in maternal age, gestational age or body mass index at sample collection (p=ns). Statistically significant differences were found between groups in mean values of systolic and diastolic blood pressure (p<0.05). No significant differences were found in interleukin-2 concentrations in the study group (68.7±29.6pg/ml) and patients in the control group (59.9±18.4pg/ml), but a slight, positive and significant correlation was found with mean systolic blood pressure (r=0.227; p<0.05).ConclusionsInterleukin-2 concentrations were similar in preeclamptic patients and healthy normotensive pregnant women (AU)

Lack of T-cell responses following autologous tumour lysate pulsed dendritic cell vaccination, in patients with relapsed osteosarcoma

BACKGROUND: Immunotherapy using autologous dendritic cell (DC) vaccination has not been systematically evaluated in osteosarcoma. We therefore conducted a phase I trial to assess feasibility, safety and tumour-specific immune responses in patients with relapsed disease. PATIENTS AND METHODS: Of 13 recruited patients with relapsed osteosarcoma, 12 received 3 weekly vaccines of autologous DCs matured with autologous tumour lysate and keyhole limpet haemocyanin (KLH), to a maximum of 6 vaccinations. An additional 3 paediatric patients afflicted with other tumour types and with relapsed disease received vaccines generated with identical methodology. Immune responses were assessed using an ELISpot assay for the detection of interferon gamma, whilst interleukin-2 and granzyme B were additionally assessed in cases where interferon-γ responses were induced. RESULTS: In total 61 vaccines, of homogeneous maturation phenotype and viability, were administered with no significant toxicity. Only in 2 out of 12 treated osteosarcoma cases was there an induction of specific T-cell immune response to the tumour, whilst a strong but non-specific immune response was induced in 1 further osteosarcoma patient. Immune response against KLH was induced in only 3 out of 12 osteosarcoma patients. In contrast, three additional non-osteosarcoma patients showed significant T-cell responses to vaccine. CONCLUSION: We have shown the strategy of DC vaccination in relapsed osteosarcoma is safe and feasible. However, significant anti-tumour responses were induced in only 2 out of 12 vaccinated patients with no evidence of clinical benefit. Comparison of results with identically treated control patients suggests that osteosarcoma patients might be relatively insensitive to DC-based vaccine treatments (AU)

Interleukin-15 enhances T-cell responses by stimulation with dendritic cells

INTRODUCTION: Cytokines play important roles in regulating immune responses. Interleukin-2 (IL-2) has usually been used as an adjuvant to enhance antitumour immune responses. However, its crucial role in activation-induced cell death, inhibition of homeostatic proliferation of CD8+ memory T cells and its notable biological side effects impair its prospect of application. IL-15 has several similar functions to IL-2 and shows potential advantages over IL-2, and is being investigated to enhance antitumour dendritic cell (DC) vaccine strategies in our ongoing studies. OBJECTIVE: In this preliminary study, we evaluated the ability of IL-15, compared with IL-2, to act as an adjuvant to enhance T-cell responses activated by DCs in vitro. MATERIALS AND METHODS: Bone marrow-derived DCs (BMDCs) were pulsed with tumour antigens and used to stimulate lymphocyte responses in the presence of IL-15 or IL-2. The activated T lymphocytes were examined by flow cytometric analysis, and interferon-γ (IFN-γ) enzyme-linked immunospot and cytotoxicity assays. RESULTS: IL-15 was observed to activate lymphocytes with comparable phenotype characteristics of activated/memory CD8+ lymphocytes, compared with IL-2. Both in primary and secondary stimulation with DCs, when using IL-15 as an adjuvant, activated lymphocytes showed higher proportions of IFN-γ-secreting subsets. In secondary stimulation with BMDCs in the presence of IL-15, the activated lymphocytes showed a stronger cytotoxicity to antigen-specific tumour target cells. CONCLUSIONS: Our study suggested that IL-15 might be a prospective adjuvant for a DC vaccine strategy against cancers. The further observation that IL-15 acts as an adjuvant for an antitumour DC vaccine strategy is worth investigating (AU)

Studies on the activating capacity of heat killed M. tuberculosis and its culture filtrate proteins on polymorphonuclear neutrophils and peripheral mononuclear cells from tuberculosis patients

En este estudio se investiga la eficacia de M. tuberculosis muerto porcalor (Mtbi) y las Proteinas del Filtrado del Cultivo (PFC) en la activación de las células mononucleares (MC) y polimorfonucleares neutrolilos (PMN)de sangre periférica de pacientes tuberculosos. Se evalua en 16 pacientes tuberculosos, HIV- y 12 controles sanos el Estallido Respiratorio, los metabolitos derivados del NO y la producción de IL-2, IL-12 y TNFeÁ por las células estimuladas. Se detecta un incremento en la concentración de TNFeÁ en el sobrenadante de cultivo (s.c.) de PMN al comparar con los valoresbasales y en la evaluada en s.c. de MC y PMN estimulados, al ser comparadas con las del grupo control, excepto para los neutrófilos estimuladoscon PFC. Se mostraron niveles aumentados de IL-12 e IL-2 en s.c. de ambas células, MC y PMN estimuladas por en PTB, mientras que no se hallarondiferencias en los s.c. de los controles. Los valores basales de Estallido Respiratorio (RB) detectada en MC y PMN de pacientes no difirieron significantivamente de los correspondientes al grupo control. La expresión del Estallido Respiratorio en ambos tipos celulares fue menor en los pacientes que en los controles, independientemente del estímulo empleado. Sedeterminaron concentraciones de nitritos más elevadas en los sobrenadantesde las MC estimuladas con Mtbi y PFC provenientes de pacientes, comparadas con las de los controles. Los datos obtenidos relacionados al estímulo de la respuesta celular, nos proporcionan información sobre la inmunidad protectiva contra el M. tuberculosis y, a la vez, aportan algunos recursos útiles para una terapia anti-tuberculosa más eficiente (AU)

The efficacy of heat-killed Mycobacterium tuberculosis (HKMtb) andits culture filtrate proteins (CFP) to activate blood mononuclear cells (MC)and polymorphonuclear neutrophils (PMN) from tuberculosis patientswas investigated. Respiratory burst, NO-derived metabolites, IL-2, IL-12and TNF-¦Á production of stimulated cells from 16 HIV- tuberculosispatients and 12 healthy controls were analyzed. Increased amounts ofTNF-¦Á in supernatants from baseline and stimulated polymorphonuclear and mononuclear cells of tuberculosis patients were detected whencompared with controls, except for CFP stimulated neutrophils. Augmented IL-2 and IL-12 levels were observed in supernatants of both stimulated MC and PMN from TBP while no differences were found in control supernatants. The patients had a lower respiratory burst responsethan the controls, for both cell types, regardless of the stimulus employed. Higher nitrite concentrations were found in HKMtb- and CFP-stimulated mononuclear supernatants from patients, compared with controls. The obtained data of the stimulated cellular responses provides usinformation about the protective immunity against Mycobacterium tuberculosis and some resources to obtain a more efficient anti-tuberculous therapy (AU)1

Aspergillosis in patients treated with monoclonal antibodies

La aspergilosis invasora es una enfermedad estrechamente relacionada con situaciones de neutropenia prolongada o el uso de corticosteroides. Sin embargo, el uso de nuevas estrategias terapéuticas, como los agente biológicos que actuan bloqueando la respuesta inmune específica, ha aumentado el riesgo de los pacientes a sufrir esta infección. La mayor parte de los casos de aspergilosis en pacientes bajo terapia de anticuerpos monoclonales se han asociado al uso de bloqueadores del factor de necrosis tumoral alfa (TNFalfa). Sin embargo, muchos otros fármacos parecen implicados en estos casos, incluyendo los inhibidores de la interleuquina 2 y bloqueadores de CD52 y CD20. En este trabajo, se hace un repaso de la fisiopatología en este tipo de pacientes como factor de riesgo de la aspergilosis, además de revisar el diagnóstico y el tratamiento de esta enfermedad(AU)

Invasive aspergillosis is a disease typically related with prolonged neutropenia or the use of corticosteroids. However, the increased use of new therapeutic modalities such as biologic agents that act by blocking specific immune pathways have put more patients at risk for invasive aspergillosis. Most cases of aspergillosis in patients taking monoclonal antibodies have been associated with the use of tumour necrosis factor (TNF)-alpha blockers. However, many more drugs have been implicated, including interleukin-2 inhibitors, and CD52 and CD20 blockers. In this manuscript we review the pathophysiology associated with an increased risk for aspergillosis in these patients, in addition to diagnostic and therapeutic considerations(AU)

Experiencia en el tratamiento de satelitosis y metástasis cutáneas en tránsito de melanoma con interleucina 2 intralesional / Experience in the Treatment of Cutaneous In-Transit Melanoma Metastases and Satellitosis with Intralesional Interleukin-2

Introducción. A pesar del mal pronóstico del melanoma metastásico, las metástasis cutáneas constituyen un grupo especial por su fácil accesibilidad que lo hace susceptible al abordaje local por parte del dermatólogo. Describimos nuestra experiencia de tratamiento intralesional con interleucina 2 (IL-2) en 7 pacientes con metástasis cutáneas de melanoma maligno. Material y métodos. Un total de 244 lesiones en 7 pacientes con satelitosis y/o metástasis cutáneas de melanoma maligno han sido tratadas con IL-2 intralesional administrada dos veces a la semana. Las dosis máximas por pacientes variaron entre los 3 y 18 millones de unidades/sesión, en función del número y tamaño de las lesiones. Resultados. Se han obtenido remisiones completas (95,9 %) o parciales (3,7 %) en la gran mayoría de lesiones tratadas, una sola lesión (0,4 %), de localización subcutánea y de mayor tamaño, no respondió al tratamiento intralesional y precisó de alcoholización y posterior extirpación quirúrgica para su resolución. Todas las respuestas parciales se observaron en lesiones de localización subcutánea y mayores de 2 cm. El tratamiento fue bien tolerado, con escasos efectos secundarios de intensidad leve (grado 1-2). Conclusiones. La IL-2 puede ser una buena opción para el tratamiento de pacientes con satelitosis y metástasis cutáneas de melanoma con elevada eficacia y escasos efectos secundarios. Las lesiones menores de 2 cm y localizadas en epidermis o dermis superficial responden mejor que las mayores de 2 cm o localizadas en el tejido celular subcutáneo. Son necesarios más estudios para establecer las dosis y pautas de tratamiento adecuadas (AU)

Introduction. Although metastatic melanoma has a poor prognosis, cutaneous metastases represent a special case given their ready accessibility, making it possible for dermatologists to apply local treatment. We report our experience with intralesional treatment with interleukin (IL) 2 in 7 patients with cutaneous metastases from malignant melanoma. Material and methods. A total of 244 lesions in 7 patients with satellitosis and/or cutaneous metastases from malignant melanoma were treated with intralesional IL-2 twice a week. The maximum dose in each patient ranged from 3 to 18 million units per session, according to the number and size of lesions. Results. Complete or partial remission was achieved in almost all lesions (95.9 % and 3.7 %, respectively). Only 1 lesion (0.4 %)—the largest and located subcutaneously—did not respond to intralesional treatment and required alcoholization and subsequent surgical removal to achieve cure. All partial responses occurred in subcutaneous lesions larger than 2 cm. Treatment was well tolerated with only a few mild side effects (grade 1-2).Conclusions. IL-2 may be an effective and well-tolerated treatment option in patients with satellitosis and cutaneous metastases from melanoma. Lesions smaller than 2 cm and located in the epidermis or superficial dermis respond better than those larger than 2 cm or located in the subcutaneous cellular tissue. More studies are necessary to establish appropriate doses and regimens (AU)

HIV-infected immunologic non-responders: can we provide a helping hand?

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Efficacy of recombinant interleukin-2 (rIL-2) in patients with advanced HIV-1 infection and blunted immune response to HAART

Objetivo. Evaluamos la eficacia de la interleucina-2 recombinante (rIL-2) en pacientes infectados por VIH, con inmunodepresión avanzada y respuesta inmune discordante al tratamiento antirretroviral de gran actividad (TARGA). El objetivo primario de evaluación fue el aumento de los linfocitos CD41 al final del tratamiento respecto al valor basal. Se evaluó, además, la seguridad y el efecto de la rIL-2 sobre las diferentes poblaciones linfocitarias. Material y métodos. Estudio de cohorte prospectivo en el que se incluyeron 19 pacientes con ARN-VIH < 50 y linfocitos CD41 < 200/mm3, estables en los 12 meses previos. Se administró rIL-2 a dosis de 4,5 3 106 mUI/día por vía subcutánea, cada 4 semanas, hasta completar 6 ciclos. Resultados. La edad media de los pacientes fue 43 años, el 64% con diagnóstico previo de sida. La media de linfocitos CD41 basal (99 células/mm3) aumentó hasta 147 células/mm3 (intervalo, 24-285) al final del tratamiento (p 5 0,002) y 180 células/mm3 (intervalo, 38-280) 18 meses después de la última dosis de rIL-2. Este aumento se asoció con una disminución en la expresión de los marcadores de activación linfocitaria, HLA-DR y CD38. Conclusión. Estos resultados sugieren que la rIL-2, en pacientes con infección por VIH avanzada y respuesta inmune discordante al TARGA, puede contribuir a la expansión de los linfocitos CD41 a través de una disminución de la activación inmunológica (AU)

Objective. The efficacy of recombinant interleukin-2 (rIL-2) was assessed in HIV-infected patients with advanced immune suppression and a discordant immune response to highly active antiretroviral therapy (HAART). The primary endpoint was median change in CD41 T-cell counts at the end of treatment as compared to baseline. Secondary endpoints were safety and changes in the various T-cell subpopulations. Material and methods. In a prospective cohort study, 19 patients with HIV-RNA < 50 copies/mL and < 200 CD41 T cells/mm3 without a significant increase in the previous 12 months were scheduled to receive 6 cycles of 4.5 3 106 IU subcutaneous rIL-2 daily for 5 consecutive days, every 4 weeks. Results. Median age was 43 years, and 64% had a previous AIDS-defining event. Median nadir and baseline CD41 cell counts were 36 and 99 cells/mm3, respectively. Three patients discontinued treatment and one experienced grade 4 side effects. CD41 T-cell counts increased to 147 cells/mm3 (range, 24-285) at 1 month following completion of treatment (P 5 0.002), and 180 cells/mm3 (range, 38-280) at 18 months (P < 0.001). This improvement was associated with a significant decrease in expression rates of the activation markers, HLA-DR and CD38. Conclusion. Our results suggest that in patients with advanced HIV-infection showing a blunted immune response to HAART, rIL-2 might increase the pool of CD41 T-cells by down-regulating the status of immune activation (AU)

Uso de fármacos biológicos en dermatosis fuera de la indicación aprobada. Segunda parte: etanercept, efalizumab, alefacept, rituximab, daclizumab, basiliximab, omalizumab y cetuximab / Off-Label Use of Biologic Agents in the Treatment of Dermatosis,Part 2: Etanercept, Efalizumab, Alefacept, Rituximab, Daclizumab, Basiliximab, Omalizumab, and Cetuximab

En los últimos años han aparecido una serie de nuevos fármacos desarrollados por biología molecular. Estos medicamentos actúan bloqueando moléculas específicas del sistema inmunológico y se desarrollan para actuar sobre dianas específicas que tienen un papel importante en la fisiopatología de determinadas enfermedades para cuyo tratamiento son aprobadas. Con el tiempo se ha ido adquiriendo experiencia con estos medicamentos en el tratamiento de dermatosis para las que no han sido diseñados, pero para las que, por compartir un mismo mecanismo fisiopatológico, pueden ser útiles. El empleo de estos medicamentos en el tratamiento de casos difíciles de numerosas enfermedades dermatológicas para las cuales no están aprobados es creciente. Esta segunda parte de la revisión analiza el uso, fuera de indicación, en el tratamiento de la dermatosis de los siguientes fármacos biológicos: etanercept, efalizumab, alefacept, rituximab, daclizumab, basiliximab, omalizumab y cetuximab

In recent years, a series of new drugs have been developed through the application of molecular biology. These drugs act by blocking specific molecules of the immune system and have been developed to act on specific targets that play an important role in the pathophysiology of the diseases in which their therapeutic use has now been approved. Over time, experience has been accumulated in the use of these drugs in the treatment of skin diseases for which they have not been approved but in which the pathophysiology suggests that they could also be effective. The use of these drugs is increasing in difficult-to-treat cases of skin diseases for which the drugs are not approved. The second part of this review of off-label use of biologic agents in dermatology considers the use of etanercept, efalizumab, alefacept, rituximab, basiliximab, omalizumab, and cetuximab