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Background: A primary barrier to curing HIV is the HIV reservoir. The leading infectious cause of death worldwide for people living with HIV is tuberculosis (TB), but we do not know how TB impacts the HIV reservoir. Methods: Participants in identification and validation cohorts were selected from previously enrolled studies at Groupe Haïtien d'Étude du Sarcome de Kaposi et des Infections Opportunistes (GHESKIO) in Port au Prince, Haiti. Intact and non-intact proviral DNA were quantified using droplet digital PCR of peripheral blood mononuclear cell (PBMC)-derived CD4+ T cells. Kruskal-Wallis tests were used to compare medians with tobit regression for censoring. Results: In the identification cohort, we found that people living with HIV with a history of active pulmonary TB (n=19) had higher levels of intact provirus than people living with HIV without a history of active TB (n=47) (median 762; IQR, 183-1173 vs 117; IQR, 24-279 intact provirus per million CD4, respectively; P=0.0001). This difference also was seen in the validation cohort (n=31), (median 102; IQR, 0-737 vs 0; IQR, 0-24.5 intact provirus per million CD4, P=0.03) for TB vs no-TB history groups, respectively. The frequencies of CD4+ T cells with any detectable proviral fragment was directly proportional to the levels of interleukin-1 beta (r=0.524, P= 0.0025) and interleukin-2 (r=0.622, P=0.0002). Conclusions: People living with HIV with a history of active pulmonary TB have more HIV pro-virus in their circulating CD4+ T cells, even years after TB cure. We need to characterize which CD4+ T cells are harboring intact provirus to consider the impact of T cell-targeting HIV cure interventions for people living in TB-endemic areas.
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BACKGROUND: In a previous work, an IL-2Rßγ biased mutant derived from human IL-2 and called IL-2noα, was designed and developed. Greater antitumor effects and lower toxicity were observed compared to native IL-2. Nevertheless, mutein has some disadvantages, such as a very short half-life of about 9-12 min, propensity for aggregation, and solubility problems. OBJECTIVE: In this study, PEGylation was employed to improve the pharmacokinetic and antitumoral properties of the novel protein. METHODS: Pegylated IL-2noα was characterized by polyacrylamide gel electrophoresis, size exclusion chromatography, in vitro cell proliferation and in vivo cell expansion bioassays, and pharmacokinetic and antitumor studies. RESULTS: IL-2noα-conjugates with polyethylene glycol (PEG) of 1.2 kDa, 20 kDa, and 40 kDa were obtained by classical acylation. No significant changes in the secondary and tertiary structures of the modified protein were detected. A decrease in biological activity in vitro and a significant improvement in half-life were observed, especially for IL-2noα-PEG20K. PEGylation of IL-2noα with PEG20K did not affect the capacity of the mutant to induce preferential expansion of T effector cells over Treg cells. This pegylated IL-2noα exhibited a higher antimetastatic effect compared to unmodified IL-2noα in the B16F0 experimental metastases model, even when administered at lower doses and less frequently. CONCLUSION: PEG20K was selected as the best modification strategy, to improve the blood circulation time of the IL-2noα with a superior antimetastatic effect achieved with lower doses.
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Interleucina-2 , Proteínas , Humanos , Polietilenglicoles/químicaRESUMEN
Abstract Background: Ivermectin may affect the levels of cytokines and immunoglobulins in sheep, considering that avermectins have an effect on the immune system. Objective: To determine whether ivermectin has an effect on cytokines and immunoglobulins in sheep. Methods: After administration of ivermectin to 10 healthy sheep, sheep-specific interferon-α, tumor necrosis factor-α, interleukin-2, interleukin-6, interleukin-10, immunoglobulin G, immunoglobulin M, and immunoglobulin E levels were measured with an ELISA reader. Results: Significant (p<0.05) fluctuations were detected in interleukin-2 and interleukin-10 levels. Transient increases (p<0.05) were measured in tumor necrosis factor-α and immunoglobulin E levels (p<0.05). Conclusion: Ivermectin may affect immune system parameters in healthy sheep; however, the effects of ivermectin administration on infected sheep should be investigated.
Resumen Antecedentes: La ivermectina puede alterar los niveles de citocinas e inmunoglobulinas en ovinos, dado que las avermectinas afectan el sistema inmunológico. Objetivo: Determinar si la ivermectina tiene algún efecto sobre las citocinas e inmunoglobulinas en ovinos. Métodos: Después de la administración de ivermectina a 10 ovejas sanas los niveles de interferón-α específico de oveja, factor de necrosis tumoral-α, interleucina-2, interleucina-6, interleucina-10, inmunoglobulina G, inmunoglobulina M, e inmunoglobulina E se midieron con un lector ELISA. Resultados: Se detectaron fluctuaciones significativas (p<0,05) en los niveles de interleucina-2 e interleucina-10. También se encontraron aumentos transitorios (p<0,05) en los niveles de factor de necrosis tumoral-α e inmunoglobulina E (p<0,05). Conclusión: la ivermectina puede afectar los parámetros del sistema inmunitario en ovejas sanas.
Resumo Antecedentes: A ivermectina pode alterar os níveis de citocinas e imunoglobulinas em ovinos, visto que as avermectinas afetam o sistema imunológico. Objetivo: Determinar o efeito da ivermectina nas citocinas e imunoglobulinas em ovinos. Métodos: Após a administração de ivermectina a 10 ovelhas saudáveis, interferon-α específico de ovelha, fator de necrose tumoral-α, interleucina-2, interleucina-6 e interleucina-10, os níveis de imunoglobulina G, imunoglobulina M e imunoglobulina E foram medidos com Leitor de ELISA. Resultados: Flutuações estatisticamente significativas (p<0,05) foram detectadas nos níveis de interkeukin-2 e interkeukin-10. Aumentos transitórios (p<0,05) foram medidos nos níveis de fator de necrose tumoral-α e imunoglobulina E (p<0,05). Conclusão: A ivermectina pode afetar parâmetros do sistema imunológico em ovinos saudáveis, entretanto, os efeitos da administração de ivermectina em ovinos infectados devem ser investigados.
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The current chapter focuses on the use of filamentous phages to display and modify biologically active cytokines, with special emphasis on directed evolution of novel variants showing improved receptor binding. Cytokines are essential protein mediators involved in cell-to-cell communication. Their functional importance and the complexity of their interactions with multichain receptors make cytokine engineering a promising tool for the discovery and optimization of therapeutic molecules. Protocols used at the laboratory are illustrated through examples of manipulation of interleukin-2 and interleukin-6, two members of the family of alpha-helix-bundle cytokines playing pivotal roles in immunity and inflammation.
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Bacteriófagos , Citocinas , Humanos , Interleucina-6 , Comunicación Celular , InflamaciónRESUMEN
Preterm birth (PB) is a leading cause of perinatal morbidity and mortality. PB prediction is performed by measuring cervical length, with a detection rate of around 70%. Although it is known that a cytokine-mediated inflammatory process is involved in the pathophysiology of PB, none screening method implemented in clinical practice includes cytokine levels as a predictor variable. Here, we quantified cytokines in cervical-vaginal mucus of pregnant women (18-23.6 weeks of gestation) with high or low risk for PB determined by cervical length, also collecting relevant obstetric information. IL-2, IL-6, IFN-γ, IL-4, and IL-10 were significantly higher in the high-risk group, while IL-1ra was lower. Two different models for PB prediction were created using the Random Forest machine-learning algorithm: a full model with 12 clinical variables and cytokine values and the adjusted model, including the most relevant variables-maternal age, IL-2, and cervical length- (detection rate 66 vs. 87%, false positive rate 12 vs. 3.33%, false negative rate 28 vs. 6.66%, and area under the curve 0.722 vs. 0.875, respectively). The adjusted model that incorporate cytokines showed a detection rate eight points higher than the gold standard calculator, which may allow us to identify the risk PB risk more accurately and implement strategies for preventive interventions.
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Nacimiento Prematuro , Embarazo , Recién Nacido , Femenino , Humanos , Nacimiento Prematuro/diagnóstico , Citocinas , Interleucina-2 , Vagina , Cuello del Útero , MocoRESUMEN
ABSTRACT Background: Cases of coronavirus disease 2019 (COVID-19) requiring hospitalization continue to appear in vulnerable populations, highlighting the importance of novel treatments. The hyperinflammatory response underlies the severity of the disease, and targeting this pathway may be useful. Herein, we tested whether immunomodulation focusing on interleukin (IL)-6, IL-17, and IL-2, could improve the clinical outcomes of patients admitted with COVID-19. Methods: This multicenter, open-label, prospective, randomized controlled trial was conducted in Brazil. Sixty hospitalized patients with moderate-to-critical COVID-19 received in addition to standard of care (SOC): IL-17 inhibitor (ixekizumab 80 mg SC/week) 1 dose every 4 weeks; low-dose IL-2 (1.5 million IU per day) for 7 days or until discharge; or indirect IL-6 inhibitor (colchicine) orally (0.5 mg) every 8 hours for 3 days, followed by 4 weeks at 0.5 mg 2x/day; or SOC alone. The primary outcome was accessed in the "per protocol" population as the proportion of patients with clinical improvement, defined as a decrease greater or equal to two points on the World Health Organization's (WHO) seven-category ordinal scale by day 28. Results: All treatments were safe, and the efficacy outcomes did not differ significantly from those of SOC. Interestingly, in the colchicine group, all participants had an improvement of greater or equal to two points on the WHO seven-category ordinal scale and no deaths or patient deterioration were observed. Conclusions: Ixekizumab, colchicine, and IL-2 were demonstrated to be safe but ineffective for COVID-19 treatment. These results must be interpreted cautiously because of the limited sample size.
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The study determined immunological indices of Giant African Land snail (Archachatina marginata) improved with fixed dose of vitamin C under acute heat stress (AHS). Prior to the AHS, vitamin C was administered for four weeks to two treatment groups, while other two treatment groups were not. Each treatment was monitored, haemolymph collected at 0, 30 and 60 minutes exposure times. Immunological cytokines: interferon gamma (IFN-γ) and interleukin 2 (IL-2); and total haemocyte counts (THC) were determined. Under AHS, vitamin C elevated (p <0.05) IFN-γ production (606.33 ± 302.86) compared to other groups with or without vitamin C administration (7.20 ± 1.58 vs. 73.20 ± 32.23 vs. 7.80 ± 1.36). IL-2 was not affected (p >0.05) by vitamin C under AHS. Highest (p <0.05) THC values was obtained with vitamin C administration under AHS, but reduced under no AHS. Exposure time affected (p <0.05) IFN-γ production and THC values, but not IL-2 (p >0.05). With fixed dose of vitamin C and exposure time, highest (p <0.05) IFN-γ values were obtained under AHS with vitamin C administration at 30 minutes and at 60 minutes in THC, compared to other groups. The study concluded that fixed dose of vitamin C at 150 mg kg-1 of feed was appropriate under AHS to boost the immune system of the animals.(AU)
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Animales , Ácido Ascórbico/administración & dosificación , Caracoles/inmunología , Relación Dosis-Respuesta Inmunológica , Alimentos Fortificados , Técnicas Inmunológicas/veterinaria , Interleucinas/inmunología , Interferones/inmunología , Respuesta al Choque Térmico/fisiología , Hemocitos/inmunologíaRESUMEN
Trypanosoma cruzi infection causes Chagas' disease in humans. The infection activates the innate and adaptative immunity in an orchestrated immune response to control parasite growth, guaranteeing host survival. Despite an effective immune response to the parasite in the acute phase, the infection progresses to a chronic stage. The parasite infects different tissues such as peripheral neurons, the brain, skeletal muscle, and heart muscle, among many others. It is evident now that tissue-specific immune responses may develop along with anti-parasite immunity. Therefore, mechanisms to regulate immunity and to ensure tissue-specific tolerance are operating during the infection. Studying those immunoregulatory mechanisms is fundamental to improve host protection or control inflammatory reactions that may lead to pathology. The role of IL-2 during T. cruzi infection is not established. IL-2 production by T cells is strongly down-modulated early in the disease by unknown mechanisms and remains low during the chronic phase of the disease. IL-2 activates NK cells, CD4, and CD8 T cells and may be necessary to immunity development. Also, the expansion and maintenance of regulatory T cells require IL-2. Thus, IL-2 may be a key cytokine involved in promoting or down-regulating immune responses, probably in a dose-dependent manner. This study blocked IL-2 during the acute T. cruzi infection by using a neutralizing monoclonal antibody. The results show that parasitemia and mortality rate was lower in animals treated with anti-IL-2. The percentages and total numbers of CD4+CD25+Foxp3+ T cells diminished within three weeks of infection. The numbers of splenic activated/memory CD4 and CD8 splenic T cells increased during the acute infection. T cells producing IFN-γ, TNF-α and IL-10 also augmented in anti-IL-2-treated infected mice. The IL-2 blockade also increased the numbers of inflammatory cells in the heart and skeletal muscles and the amount of IL-17 produced by heart T cells. These results suggest that IL-2 might be involved in the immune regulatory response during the acute T. cruzi infection, dampening T cell activation through the expansion/maintenance of regulatory T cells and regulating IL-17 production. Therefore, the IL-2 pathway is an attractive target for therapeutic purposes in acute and chronic phases of Chagas' disease.
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Enfermedad de Chagas , Trypanosoma cruzi , Animales , Linfocitos T CD8-positivos , Enfermedad de Chagas/tratamiento farmacológico , Interleucina-2 , Ratones , ParasitemiaRESUMEN
Liver involvement in COVID-19 is not yet well-understood, but elevations in liver transaminases have been described to occur in 14-53% of the cases and are more frequently seen in severe disease. This cross-sectional study explored the relationship between the elevations in liver transaminases and inflammatory parameters in 209 adults with COVID-19. Demographic and clinical data, serum levels of inflammatory cytokines and liver aminotransferases were analyzed. Three groups were formed according to the liver transaminase abnormalities: (I) Normal transaminases, (II) Borderline transaminases elevation, and (III) Mild to severe transaminases elevation. Altered liver transaminases were directly related to disease severity, showing association with the NEWS2 score at admission and greater need for ICU or death. Moreover, higher levels of IL-2 and CRP were associated with borderline transaminases elevations, whereas higher levels of IL-10 and Neutrophil to Lymphocyte ratio were associated with mild to severe transaminases elevation. These results reinforce the importance of liver transaminases in patients with COVID-19 as a complementary marker for disease severity and also point to them as a parameter reflecting the continuous dynamics between viral infection and the immune response.
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Cigarette smoke (CS) affects immune functions, leading to severe outcomes in smokers. Robust evidence addresses the immunotoxic effects of combustible tobacco products. As heat-not-burn tobacco products (HNBT) vaporize lower levels of combustible products, we here compared the effects of cigarette smoke (CS) and HNBT vapor on Jurkat T cells. Cells were exposed to air, conventional cigarettes or heatsticks of HNBT for 30 min and were stimulated or not with phorbol myristate acetate (PMA). Cell viability, proliferation, reactive oxygen species (ROS) production, 8-OHdG, MAP-kinases and nuclear factor κB (NFκB) activation and metallothionein expression (MTs) were assessed by flow cytometry; nitric oxide (NO) and cytokine levels were measured by Griess reaction and ELISA, respectively. Levels of metals in the exposure chambers were quantified by inductively coupled plasma mass spectrometry. MT expressions were quantified by immunohistochemistry in the lungs and liver of C57Bl/6 mice exposed to CS, HNBT or air (1 h, twice a day for five days: via inhalation). While both CS and HBNT exposures increased cell death, CS led to a higher number of necrotic cells, increased the production of ROS, NO, inflammatory cytokines and MTs when compared to HNBT-exposed cells, and led to a higher expression of MTs in mice. CS released higher amounts of metals. CS and HNBT exposures decreased PMA-induced interleukin-2 (IL-2) secretion and impaired Jurkat proliferation, effects also seen in cells exposed to nicotine. Although HNBT vapor does not activate T cells as CS does, exposure to both HNBT and CS suppressed proliferation and IL-2 release, a pivotal cytokine involved with T cell proliferation and tolerance, and this effect may be related to nicotine content in both products.
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Nicotiana , Productos de Tabaco , Animales , Calor , Ratones , Humo/efectos adversos , FumarRESUMEN
El síndrome de activación macrofágica (SAM) presenta criterios clínicos y de laboratorio establecidos. Presentamos el caso de un adolescente varón con debut de Lupus eritematoso generalizado pediátrico grave, donde su manifestación principal fue un SAM y el receptor de interleucina 2 soluble en suero (IL-2rs) o CD25 soluble (CD25s) aumentado resultó clave en la confirmación diagnóstica, en el tratamiento y pronóstico de su enfermedad. Sin embargo, este receptor de citocinas no se mide habitualmente en la práctica clínica.
Macrophage activation syndrome (MAS) presents established clinical and laboratory criteria. We present the case of a male adolescent with the onset of severe pediatric systemic Lupus erythematosus, manifested mainly by MAS and how a laboratory marker, serum soluble interleukin-2 receptor (IL-2rs) or altered soluble CD25(CD25s), played a key role in treatment and prognosis of the disease. However, this cytokine receptor is rarely measured in clinical practice.
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Humanos , Masculino , Niño , Linfohistiocitosis Hemofagocítica/diagnóstico , Linfohistiocitosis Hemofagocítica/terapia , Síndrome de Activación Macrofágica/diagnóstico , Síndrome de Activación Macrofágica/terapia , Tórax/diagnóstico por imagen , Radiografía Torácica/métodos , Receptores de Interleucina-2 , Síndrome de Activación Macrofágica/patología , Lupus Eritematoso SistémicoRESUMEN
INTRODUCTION AND AIM: The interleukin-2 receptor antagonist; basiliximab is used to allow delayed introduction of Calcineurin inhibitors (CNI) after liver transplantation and thus delay their renal insult. However, there is only little evidence for the safety and the efficacy of this regimen. This study aimed to evaluate the effectiveness and safety of basiliximab induction in liver transplantation. MATERIALS AND METHODS: This study included 89 patients who were classified into two groups: standard triple immunosuppression (IS) regimen of steroid, tacrolimus (TAC) and mycophenolate mofetil (MMF) (n = 47) and induction IS regimen of basiliximab, low dose steroids and MMF with delayed introduction of CNI (n = 42). All patients were followed after liver transplantation for at least six months or until death. RESULTS: There were no significant differences in patient survival, graft dysfunction, infection rate or type, or wound healing between both groups. The acute rejection rate was equivalent in both groups. Renal dysfunction in the first six months post-transplant was less in the basiliximab group in comparison to the other group (7.1% and 19.1% respectively). CONCLUSION: Basiliximab-induced IS protocol is a safe regimen that reduces medium-term renal dysfunction and achieves similar survival without increasing the acute rejection or infection rate in liver transplantation recipients.
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Basiliximab/uso terapéutico , Rechazo de Injerto/prevención & control , Supervivencia de Injerto/efectos de los fármacos , Inmunosupresores/uso terapéutico , Trasplante de Hígado , Adulto , Basiliximab/efectos adversos , Inhibidores de la Calcineurina/uso terapéutico , Quimioterapia Combinada , Egipto , Femenino , Rechazo de Injerto/inmunología , Rechazo de Injerto/mortalidad , Humanos , Inmunosupresores/efectos adversos , Trasplante de Hígado/efectos adversos , Trasplante de Hígado/mortalidad , Masculino , Persona de Mediana Edad , Ácido Micofenólico/uso terapéutico , Esteroides/uso terapéutico , Tacrolimus/uso terapéutico , Factores de Tiempo , Resultado del TratamientoRESUMEN
The objective of this study was to assess the effects of auto-lysed yeast and yeast extract on performance and immune responses of cows in hot climate in the early lactation period. Twenty five lactating dairy cows randomly assigned to 5 groups and 5 replicates. Cows received basal diet with or without auto-lysed yeast (20 or 40 g/d/head) or yeast extract (20 or 40 g/d/head) as on top-dressed. There were no differences for daily dry matter intake, milk production milk fat and the counts of red blood cells and white blood cells among treatments (p > 0.05). There were significant differences among treatments for immunoglobulin G (IgG) level, lymphocyte and neutrophil percentages. Yeast extract had no effect on IgG level, but auto-lysed yeast increased IgG level and neutrophil percentage and decreased lymphocyte percentage (p < 0.05). The highest relative interleukin-2 gene expression was for cows received auto-lysed yeast at the level of 40 g/d/head. Yeast extract had no significant effect on interleukin-2 gene expression as compared to the control group. It was concluded that auto-lysed yeast at the level of 40 g/d/head had no effect on performance, but it could positively influence on immune response of lactating dairy cows in hot climate during early period of lactation.~ien
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Femenino , Animales , Bovinos , Bovinos/fisiología , Bovinos/genética , Bovinos/sangre , Inmunoglobulina G , Levaduras , Respuesta al Choque TérmicoRESUMEN
The objective of this study was to assess the effects of auto-lysed yeast and yeast extract on performance and immune responses of cows in hot climate in the early lactation period. Twenty five lactating dairy cows randomly assigned to 5 groups and 5 replicates. Cows received basal diet with or without auto-lysed yeast (20 or 40 g/d/head) or yeast extract (20 or 40 g/d/head) as on top-dressed. There were no differences for daily dry matter intake, milk production milk fat and the counts of red blood cells and white blood cells among treatments (p > 0.05). There were significant differences among treatments for immunoglobulin G (IgG) level, lymphocyte and neutrophil percentages. Yeast extract had no effect on IgG level, but auto-lysed yeast increased IgG level and neutrophil percentage and decreased lymphocyte percentage (p < 0.05). The highest relative interleukin-2 gene expression was for cows received auto-lysed yeast at the level of 40 g/d/head. Yeast extract had no significant effect on interleukin-2 gene expression as compared to the control group. It was concluded that auto-lysed yeast at the level of 40 g/d/head had no effect on performance, but it could positively influence on immune response of lactating dairy cows in hot climate during early period of lactation.(AU)~ien
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Animales , Femenino , Bovinos , Bovinos/sangre , Bovinos/genética , Bovinos/fisiología , Levaduras , Inmunoglobulina G , Respuesta al Choque TérmicoRESUMEN
Immunosenescence has been described as age-associated changes in the immune function which are thought to be responsible for the increased morbidity with age. Human Natural Killer (NK) cells are a specialized heterogeneous subpopulation of lymphocytes involved in immune defense against tumor and microbial diseases. Interestingly, aging-related NK cell dysfunction is associated with features of aging such as tumor incidence, reduced vaccination efficacy, and short survival due to infection. It is known that NK cell effector functions are critically dependent on cytokines and metabolic activity. Our aim was to determine whether there is a difference in purified human NK cell function in response to high concentration of IL-2 between young and elder donors. Here, we report that the stimulation of human NK cells with IL-2 (2000â¯U/mL) enhance NK cell cytotoxic activity from both young and elderly donors. However, while NK cells from young people responded to IL-2 signaling by increasing mitochondrial mass and mitochondrial membrane potential, no increase in these mitochondrial functional parameters was seen in purified NK cells from elderly subjects. Moreover, as purified NK cells from the young exhibited an almost three-fold increase in PGC-1α expression after IL-2 (2000â¯U/mL) stimulation, PGC-1α expression was inhibited in purified NK cells from elders. Furthermore, this response upon PGC-1α expression after IL-2 stimulation promoted an increase in ROS production in NK cells from elderly humans, while no increase in ROS production was observed in NK cells of young donors. Our data show that IL-2 stimulates NK cell effector function through a signaling pathway which involves a PGC-1α-dependent mitochondrial function in young NK cells, however it seems that NK cells from older donors exhibit an altered IL-2 signaling which affects mitochondrial function associated with an increased production of ROS which could represent a feature of NK cell senescence.
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Células Asesinas Naturales/metabolismo , Mitocondrias/metabolismo , Biogénesis de Organelos , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Anciano , Anciano de 80 o más Años , Células Cultivadas , Inhibidores Enzimáticos/farmacología , Femenino , Humanos , Interleucina-2/farmacología , Células K562 , Células Asesinas Naturales/efectos de los fármacos , Masculino , Potencial de la Membrana Mitocondrial , Persona de Mediana Edad , Mitocondrias/efectos de los fármacos , ATPasas de Translocación de Protón Mitocondriales/antagonistas & inhibidores , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Transducción de Señal , Regulación hacia ArribaRESUMEN
The current chapter focuses on the use of filamentous phages to display, modify, and characterize cytokines, which are proteins belonging to a versatile group of essential mediators involved in cell-cell communication. Cytokines exhibit a considerable diversity, both in functions and in structural features underlying their biological effects. A broad variety of cytokines have been successfully displayed on phages, allowing the high-throughput study of their binding properties and biological activities and the discovery of novel therapeutics through directed evolution. The technical singularities and some potential applications of cytokine phage display are illustrated here with the case of Interleukin-2, a prototypic member of the four-alpha-helix bundle cytokine family playing a pivotal role in the immune response and having a long history of therapeutic use.
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Interleucina-2/genética , Interleucina-2/inmunología , Biblioteca de Péptidos , Animales , Línea Celular , Humanos , Estructura Secundaria de ProteínaRESUMEN
miRNAs appear to play an important role in controlling the expression of several genes, and they are a potential biomarker and prognostic tool in gastric diseases. We analyzed 53 controls, 86 patients with gastritis, and 19 patients with gastric cancer. Real-time-PCR was used to determine the expression levels of miRNA-146a, miRNA-155, IL-2, and TNF-α. The subsequent analysis of the target genes was performed using the bioinformatics approach. There was no difference in IL-2 expression between the groups. However, there was a significant increase in TNF-α expression in the gastritis group relative to the control and a significant decrease in the gastric cancer group relative to the control. There was also a statistically significant increase in miRNA-146a and miRNA-155 expression in the gastritis group relative to the control, but not in the gastric cancer group. Similar results were found when the presence of H. pylori was considered. The data revealed an increase in miRNA-146a and miRNA-155 expression but not enough to control the expression of TNF-α. The presence of H. pylori was found to affect increases in TNF-α and microRNA expression, and miRNA-146a and miRNA-155 alone were not able to eliminate bacteria or restore tissue homeostasis.
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Infecciones por Helicobacter/genética , Interleucina-2/genética , MicroARNs/genética , Neoplasias Gástricas/genética , Factor de Necrosis Tumoral alfa/genética , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Gastritis/genética , Infecciones por Helicobacter/complicaciones , Humanos , Inflamación/genética , Masculino , Persona de Mediana Edad , Neoplasias Gástricas/microbiologíaRESUMEN
Histoplasmosis is a common endemic mycosis that is usually asymptomatic but occasionally results in severe illness. Histoplasmosis and its causative agent, Histoplasma capsulatum, are found worldwide but rarely in Japan. In recent years, however, the number of histoplasmosis patients in Japan has increased. In addition, to our knowledge, there are no previous reports of increased serum soluble interleukin-2 receptor (sIL-2R) levels in patients with histoplasmosis. We report a case series of histoplasmosis in three Japanese temporary workers in Manzanillo, Mexico. All three patients developed a persistent high fever and general fatigue. Laboratory tests showed increased C-reactive protein levels and mild liver dysfunction. All patients also showed increased soluble interleukin-2 receptor (sIL-2R) levels. Chest computed tomography revealed multiple nodules in both lung fields. All patients were positive for serum anti-Histoplasma antibodies, and two patients were positive for Histoplasma on polymerase chain reaction tests. After treatment that included antifungals, their conditions gradually improved and laboratory data normalized. Although one patient developed respiratory failure, this patient recovered with antifungal therapy in combination with methylprednisolone. Serum sIL-2R levels in all patients gradually declined to normal levels, indicating their recovery from Histoplasma infection. From our experience with these patients, sIL-2R levels may be a useful biomarker for patients with histoplasmosis.
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Biomarcadores/sangre , Histoplasmosis/sangre , Receptores de Interleucina-2/sangre , Adulto , Anciano , Proteína C-Reactiva/metabolismo , Histoplasmosis/patología , Histoplasmosis/fisiopatología , Humanos , Japón/etnología , Masculino , México , Persona de Mediana Edad , Enfermedad Relacionada con los ViajesRESUMEN
Linfocitopenia CD4 idiopática (LCI) é uma imunodeficiência rara e grave caracterizada por uma diminuição inexplicável da contagem absoluta de linfócitos T CD4, a qual está associada a infecções oportunistas. Existem poucos relatos de casos na literatura que descrevem a IL2 como uma opção terapêutica em infecções oportunistas associadas à LCI. Relatamos os benefícios da adição de IL2 ao tratamento padrão em um paciente com ICL e infecções oportunistas. Um homem de 38 anos de idade foi internado por acidente vascular cerebral isquêmico devido à vasculite infecciosa. A análise do líquido cefalorraquidiano mostrou meningite neutrofílica. Cultura e PCR foram positivos para Mycobacterium tuberculosis. A tomografia de tórax foi compatível com tuberculose pulmonar. O paciente também apresentava candidíase oral, onicomicose e dermatite seborreica. A contagem de células sanguíneas mostrou linfocitopenia. O tratamento padronizado para tuberculose disseminada (RIPE) e fluconazol foram iniciados e mantidos em casa após a alta do paciente. Após cinco meses de seguimento, o paciente foi encaminhado ao imunologista clínico, pois não apresentava melhora clínica significativa, tendo sido hospitalizado diversas vezes. A avaliação imunológica mostrou uma contagem sanguínea de CD4 T consistentemente inferior a 100 células/mm3 e o diagnóstico de LCI foi confirmado (linfocitopenia inexplicável com menos de 300 células/mm3 ou menos de 20% de células T CD4+ em mais de uma ocasião com pelo menos 2 meses de intervalo). O paciente também apresentava episódios raros de linfocitopenia de células B e hipogamaglobulinemia, tendo recebido gamaglobulina. Como tratamento adjuvante, a IL2 subcutânea foi associada ao tratamento padronizado. Até agora, o paciente recebeu cinco ciclos consecutivos de IL2, mostrando melhora clínica e aumento da contagem de células T CD4 no sangue, atingindo um valor máximo de 401 células/mm3. As células CD8, B e natural killer também aumentaram. Novas análises do líquido cefalorraquidiano foram normais, e a cultura de Mycobacterium tuberculosis e a PCR foram negativas. Nosso paciente com infecções oportunistas associadas à LCI apresentou evolução laboratorial e clínica favoráveis após a adição de IL2 ao tratamento padrão. Este relato de caso apoia o uso de IL2 como um coadjuvante seguro e potencialmente eficaz para infecções oportunistas associadas à LCI. O caso destaca a importância da avaliação e acompanhamento de pacientes com suspeita de imunodeficiência por imunoalergologistas.
Idiopathic CD4 T lymphocytopenia (ICL) is a rare and severe immunodeficiency disorder characterized by an unexplained decrease of absolute CD4 T-lymphocyte cell counts, which is associated with opportunistic infections. There are few case reports in the literature describing the use of interleukin 2 (IL2) as a therapeutic option in ICL-associated opportunistic infections. We report the benefits of adding IL2 to the standard treatment in a patient with ICL and opportunistic infections. A 38-year-old male patient was admitted with ischemic stroke due to infectious vasculitis. Cerebrospinal fluid analysis revealed neutrophilic meningitis. Culture and PCR were positive for Mycobacterium tuberculosis. Chest CT was compatible with pulmonary tuberculosis. The patient also presented oral candidiasis, onychomycosis, and seborrheic dermatitis. Blood cell count revealed lymphocytopenia. Standardized treatment for disseminated tuberculosis (RIPE therapy) and fluconazole were initiated and maintained at home after the patient's discharge. After five months of follow-up, the patient was referred to a clinical immunologist, due to the absence of significant clinical improvement, with multiple hospitalizations over the follow-up period. Immunological assessment showed CD4 T cell counts consistently below 100 cells/mm3, and the diagnosis of ICL was confirmed (unexplained lymphocytopenia with less than 300 cells/mm3 or less than 20% of CD4+ T cells on more than one occasion at least 2 months apart). The patient also presented rare episodes of B cell lymphocytopenia and hypogammaglobulinemia, treated with gammaglobulin. As an adjuvant treatment, subcutaneous IL2 was added to the standard treatment. So far the patient underwent five consecutive cycles of IL2, showing clinical improvement and increased CD4 T cell counts, reaching a maximum value of 401 cells/mm3. CD8, B and natural killer cells also increased. New cerebrospinal fluid analyses were normal, and new Mycobacterium tuberculosis culture and PCR were negative. Our patient had opportunistic infections associated with ICL and presented favorable laboratory and clinical outcomes after the association of IL2 to the standard treatment. This case report supports the use of IL2 as a safe and potentially effective adjuvant treatment for ICL-associated opportunistic infections. The case highlights the importance of immunological assessment and follow-up of patients with suspected immunodeficiency.