Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 6.410
Filtrar
1.
Tumour Biol ; 42(1): 1010428319901052, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31959092

RESUMEN

Feline invasive mammary carcinomas are characterized by their high clinical aggressiveness, rare expression of hormone receptors, and pathological resemblance to human breast cancer, especially triple-negative breast cancer (negative to estrogen receptor, progesterone receptor, and epidermal growth factor receptor type 2). Recent gene expression studies of triple-negative breast cancers have highlighted their heterogeneity and the importance of immune responses in their biology and prognostic assessment. Indeed, regulatory T cells may play a crucial role in producing an immune-suppressed microenvironment, notably in triple-negative breast cancers. Feline invasive mammary carcinomas arise spontaneously in immune-competent animals, in which we hypothesized that the immune tumor microenvironment also plays a role. The aims of this study were to determine the quantity and prognostic value of forkhead box protein P3-positive peritumoral and intratumoral regulatory T cells in feline invasive mammary carcinomas, and to identify an immune-suppressed subgroup of triple-negative basal-like feline invasive mammary carcinomas. One hundred and eighty female cats with feline invasive mammary carcinomas, treated by surgery only, with 2-year follow-up post-mastectomy, were included in this study. Forkhead box protein P3, estrogen receptor, progesterone receptor, Ki-67, epidermal growth factor receptor type 2, and cytokeratin 14 expression were assessed by automated immunohistochemistry. Peritumoral regulatory T cells were over 300 times more abundant than intratumoral regulatory T cells in feline invasive mammary carcinomas. Peritumoral and intratumoral regulatory T cells were associated with shorter disease-free interval and overall survival in both triple-negative (ER-, PR-, HER2-, N = 123 out of 180) and luminal (ER+ and/or PR+, N = 57) feline invasive mammary carcinomas. In feline triple-negative basal-like (CK14+) mammary carcinomas, a regulatory T-cell-enriched subgroup was associated with significantly poorer disease-free interval, overall survival, and cancer-specific survival than regulatory T-cell-poor triple-negative basal-like feline invasive mammary carcinomas. High regulatory T-cell numbers had strong and negative prognostic value in feline invasive mammary carcinomas, especially in the triple-negative basal-like subgroup, which might contain a "basal-like immune-suppressed" subtype, as described in triple-negative breast cancer. Cats with feline invasive mammary carcinomas may thus be interesting spontaneous animal models to investigate new strategies of cancer immunotherapy in an immune-suppressed tumor microenvironment.


Asunto(s)
Neoplasias Mamarias Animales/patología , Neoplasias de la Mama Triple Negativas/patología , Animales , Gatos , Modelos Animales de Enfermedad , Femenino , Humanos , Inmunohistoquímica/métodos , Inmunosupresión/métodos , Neoplasias Mamarias Animales/metabolismo , Pronóstico , Receptores Estrogénicos/metabolismo , Receptores de Progesterona/metabolismo , Estudios Retrospectivos , Linfocitos T Reguladores/metabolismo , Linfocitos T Reguladores/patología , Neoplasias de la Mama Triple Negativas/metabolismo , Microambiente Tumoral/fisiología
2.
Ann Hematol ; 99(3): 421-429, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31984437

RESUMEN

ß-thalassemia major is one of the most common hematologic disorders in the world. It causes severe anemia and patients require regular blood transfusions, which causes different complications such as iron overload and alloimmunization. Regulatory T cells (Tregs) have an important role in regulation of immune responses. FoxP3 is the major marker of Tregs and its expression can be influenced by different factors. GDF-15 is another gene that plays a role in iron homeostasis and regulation of immune system in different diseases. The aim of this study was to assess the frequency of Tregs and FoxP3/GDF-15 gene expression in ß-thalassemia major patients with and without alloantibody as well as its correlation with different factors such as serum ferritin and folate levels. This study was conducted on 68 ß-thalassemia major patients with and without alloantibodies in comparison with 20 healthy individuals with matched age and sex as control group. Enzyme-linked immunosorbent assay (ELISA), flow cytometry, and real-time PCR were performed in order to evaluate serum ferritin and folate levels, frequency of Tregs, and the expression of FoxP3 and GDF-15 genes, respectively. The percentage and absolute count of Tregs were increased in patients compared with controls (P = 0.0003), but there was no difference between responders and non-responders (P > 0.05). The Tregs count correlated positively with serum ferritin. No correlation was observed between target genes and serum ferritin and folate, but there was a positive significant correlation between the expression of FoxP3 and GDF-15 genes, which shows the immunosuppressive role of GDF-15.


Asunto(s)
Ferritinas , Ácido Fólico , Factores de Transcripción Forkhead , Regulación de la Expresión Génica/inmunología , Factor 15 de Diferenciación de Crecimiento , Isoanticuerpos , Linfocitos T Reguladores , Talasemia beta , Adolescente , Adulto , Niño , Femenino , Ferritinas/sangre , Ferritinas/inmunología , Ácido Fólico/sangre , Ácido Fólico/inmunología , Factores de Transcripción Forkhead/biosíntesis , Factores de Transcripción Forkhead/inmunología , Factor 15 de Diferenciación de Crecimiento/biosíntesis , Factor 15 de Diferenciación de Crecimiento/inmunología , Humanos , Isoanticuerpos/sangre , Isoanticuerpos/inmunología , Masculino , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Linfocitos T Reguladores/patología , Talasemia beta/sangre , Talasemia beta/inmunología , Talasemia beta/patología
3.
Int J Cancer ; 146(7): 1993-2006, 2020 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-31709528

RESUMEN

Regulatory T cells (Tregs) are crucial for the maintenance of peripheral tolerance, but they also limit beneficial responses through cancer-induced immunoediting. The roles of Treg subsets in cervical squamous cell carcinoma (CSCC) are currently unknown. Here, we aimed to perform an extensive study with an increased resolution of the Treg compartment in the peripheral blood and tumor tissues of CSCC patients. We first identified that an HLADRhi Treg population in the peripheral blood was significantly increased in CSCC patients compared to precancer patients and healthy donors. We found that HLADRhi Tregs express high levels of a panel of inhibition and activation markers and the TCR-responsive transcription factors BATF and IRF4. However, this Treg subset showed reduced calcium influx after TCR crosslinking. In addition, HLADRhi Tregs are highly proliferative and vulnerable to apoptosis. Further studies demonstrated that the HLADRhi Tregs display high levels of suppressive activity. Quantitative multiplexed immunohistochemistry revealed that an increase in the number of tumor-infiltrating HLADRhi Tregs is associated with unfavorable classical risk parameters of advanced disease stage and stromal invasion. Context-based quantification revealed that a high frequency of stromal HLADRhi Tregs in patients is significantly associated with worse progression-free survival. In the current study, we characterized a population of highly activated and immunosuppressive HLADRhi Tregs in CSCC patients. An increased HLADRhi Treg frequency may be a potential biomarker to stratify CSCC patients and evaluate therapeutic efficacies in personalized immuno-oncology studies.


Asunto(s)
Antígenos HLA-DR/metabolismo , Inmunomodulación , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Neoplasias del Cuello Uterino/etiología , Neoplasias del Cuello Uterino/metabolismo , Apoptosis , Biomarcadores , Progresión de la Enfermedad , Femenino , Antígenos HLA-DR/inmunología , Humanos , Inmunohistoquímica , Activación de Linfocitos , Recuento de Linfocitos , Linfocitos Infiltrantes de Tumor/patología , Fenotipo , Pronóstico , Microambiente Tumoral/inmunología , Neoplasias del Cuello Uterino/mortalidad
4.
Scand J Immunol ; 91(3): e12853, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31793005

RESUMEN

What is the evolutionary mechanism for the TCR-MHC-conserved interaction? We extend Dembic's model (Dembic Z. In, Scand J Immunol e12806, 2019) of thymus positive selection for high-avidity anti-self-MHC Tregs among double (CD4 + CD8+)-positive (DP) developing thymocytes. This model is based on competition for self-MHC (+ Pep) complexes presented on cortical epithelium. Such T cells exit as CD4 + CD25+FoxP3 + thymic-derived Tregs (tTregs). The other positively selected DP T cells are then negatively selected on medulla epithelium removing high-avidity anti-self-MHC + Pep as T cells commit to CD4 + or CD8 + lineages. The process is likened to the competitive selection and affinity maturation in Germinal Centre for the somatic hypermutation (SHM) of rearranged immunoglobulin (Ig) variable region (V[D]Js) of centrocytes bearing antigen-specific B cell receptors (BCR). We now argue that the same direct SHM processes for TCRs occur in post-antigenic Germinal Centres, but now occurring in peripheral pTregs. This model provides a potential solution to a long-standing problem previously recognized by Cohn and others (Cohn M, Anderson CC, Dembic Z. In, Scand J Immunol e12790, 2019) of how co-evolution occurs of species-specific MHC alleles with the repertoire of their germline TCR V counterparts. We suggest this is not by 'blind', slow, and random Darwinian natural selection events, but a rapid structured somatic selection vertical transmission process. The pTregs bearing somatic TCR V mutant genes then, on arrival in reproductive tissues, can donate their TCR V sequences via soma-to-germline feedback as discussed in this journal earlier. (Steele EJ, Lindley RA. In, Scand J Immunol e12670, 2018) The high-avidity tTregs also participate in the same process to maintain a biased, high-avidity anti-self-MHC germline V repertoire.


Asunto(s)
Alelos , Complejo Mayor de Histocompatibilidad/genética , Complejo Mayor de Histocompatibilidad/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Especificidad del Receptor de Antígeno de Linfocitos T , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Animales , Diferenciación Celular , Selección Clonal Mediada por Antígenos , Evolución Molecular , Centro Germinal/citología , Centro Germinal/inmunología , Centro Germinal/metabolismo , Humanos , Mamíferos , Mutación , Unión Proteica , Receptores de Antígenos de Linfocitos T/genética , Timocitos/inmunología , Timocitos/metabolismo
5.
Life Sci ; 241: 117101, 2020 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-31778687

RESUMEN

AIMS: Ten-eleven-translocation (Tet) proteins are 5-methylcytosine oxidases and have profound impact on DNA methylation and genes expression. This study aimed to investigate the role of Tet2 and its association with Foxp3 DNA methylation in regulatory T (Treg) cell of allergic rhinitis (AR). MATERIALS AND METHODS: CD4+CD25+Treg cells were sorted from peripheral blood lymphocytes drawn from AR patients and spleen lymphocytes drawn from OVA-exposed mice by flow cytometry. Tet2 and Foxp3 expressions were studied in sorted Treg cells. DNA methylation of CpG sites in Foxp3 in Treg cells was analyzed by pyrosequencing. TET2 protein binding to Foxp3 DNA in Treg cells was detected by chromatin immunoprecipitation followed by quantitative PCR (ChIP-qPCR). KEY FINDINGS: Treg cells drawn from AR patients and OVA-exposed mice showed reduction in cells counts, expression of Foxp3 mRNA and protein and down-regulation of Tet2, compared with the controls. Hypermethylation of Foxp3 TSDR and decline of TET2 binding to Foxp3 TSDR, but not promoter, were noted in Treg cells of OVA-exposed mice. Significant negative correlations between Tet2 expression and Foxp3 TSDR methylation, Foxp3 TSDR methylation and Foxp3 expression, and positive correlation between Foxp3 expression and Treg cells percentage were demonstrated by correlation analysis. SIGNIFICANCE: This study demonstrated that down-regulation of Tet2 was associated with higher methylation level of Foxp3 TSDR, reduction in Foxp3 expression and Treg cells percentage in AR, suggesting that Tet2 probably modulated the function of Treg cells in AR through Foxp3 methylation.


Asunto(s)
Metilación de ADN , Proteínas de Unión al ADN/genética , Factores de Transcripción Forkhead/genética , Proteínas Proto-Oncogénicas/genética , Rinitis Alérgica/sangre , Linfocitos T Reguladores/patología , Adolescente , Adulto , Anciano , Animales , Estudios de Casos y Controles , Proteínas de Unión al ADN/metabolismo , Modelos Animales de Enfermedad , Regulación hacia Abajo , Femenino , Factores de Transcripción Forkhead/metabolismo , Regulación de la Expresión Génica , Humanos , Inmunoglobulina E/sangre , Ratones Endogámicos C57BL , Persona de Mediana Edad , Mucosa Nasal/patología , Ovalbúmina/toxicidad , Proteínas Proto-Oncogénicas/metabolismo , Rinitis Alérgica/genética , Rinitis Alérgica/inmunología , Linfocitos T Reguladores/metabolismo
6.
Immunology ; 159(2): 205-220, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31642515

RESUMEN

Regulatory T (Treg) cells induce immunologic tolerance by suppressing effector functions of conventional lymphocytes in the periphery. On the other hand, immune silencing is mediated by recognition of phosphatidylserine (PS) on apoptotic cells by phagocytes. Here we describe expression of the PS-binding protein Annexin V (ANXA5) in CD4+  CD25hi Treg cells at the mRNA and protein levels. CD4+  ANXA5+ T cells constitute about 0·1%-0·6% of peripheral blood CD3+ T cells, exhibit co-expression of several Treg markers, such as Forkhead box P3, programmed cell death protein-1, cytotoxic T-lymphocyte antigen-4 and CD38. In vitro, ANXA5+ Treg cells showed enhanced adhesion to PS+ endothelial cells. Stimulated by anti-CD3 and PS+ syngeneic antigen-presenting cells CD4+  ANXA5+ T cells expanded in the absence of exogenous interleukin-2. CD4+  ANXA5+ T cells suppressed CD4+  ANXA5- T-cell proliferation and mammalian target of rapamycin phosphorylation, partially dependent on cell contact. CD4+  ANXA5+ T-cell-mediated suppression was allo-specific and accompanied by an increased production of anti-inflammatory mediators. In vivo, using a model of delayed type hypersensitivity, murine CD4+  ANXA5+ T cells inhibited T helper type 1 responses. In conclusion, we report for the first time expression of ANXA5 on a subset of Treg cells that might bridge classical regulatory Treg function with immune silencing.


Asunto(s)
Anexina A5/metabolismo , Hipersensibilidad Retardada/inmunología , Activación de Linfocitos , Linfocitos T Reguladores/metabolismo , Animales , Anexina A5/genética , Anexina A5/inmunología , Adhesión Celular , Proliferación Celular , Células Cultivadas , Citocinas/inmunología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Células Endoteliales/inmunología , Células Endoteliales/metabolismo , Humanos , Hipersensibilidad Retardada/genética , Hipersensibilidad Retardada/metabolismo , Masculino , Ratones Endogámicos C57BL , Fenotipo , Fosfatidilserinas/metabolismo , Fosforilación , Transducción de Señal , Linfocitos T Reguladores/inmunología , Serina-Treonina Quinasas TOR/metabolismo , Células TH1/inmunología , Células TH1/metabolismo
7.
Immunology ; 159(2): 231-241, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31713233

RESUMEN

Regulatory T (Treg) cell-specific deletion of a gene of interest is a procedure widely used to study mechanisms controlling Treg development, homeostasis and function. Accordingly, several transgenic mouse lines have been generated that bear the Cre recombinase under control of the Foxp3 promoter either as a random transgene insertion or knocked into the endogenous Foxp3 locus, with the Foxp3YFP-Cre strain of mice being one of the most widely used. In an attempt to generate Treg cells that lacked expression of the insulin receptor (Insr), we crossed Foxp3YFP-Cre mice with Insrfl/fl mice. Using a conventional two-band PCR genotyping method we found that offspring genotypes did not correspond to the expected Mendelian ratios. We therefore developed a quantitative PCR-based genotyping method to investigate possible ectopic recombination outside the Treg lineage. With this method we found that ~50% of the F1 -generation mice showed evidence of ectopic recombination and that ~10% of the F2 -generation mice had germline Cre recombination activity leading to a high frequency of offspring with global Insr deletion. Use of the quantitative PCR genotyping method enabled accurate selection of mice without ectopic recombination and only the desired Treg cell-specific Insr deletion. Our data highlight the need to use genotyping methods that allow for assessment of possible ectopic recombination driven by the Foxp3YFP-Cre allele, particularly when studying genes that are systemically expressed.


Asunto(s)
Proteínas Bacterianas/genética , Factores de Transcripción Forkhead/genética , Integrasas/genética , Proteínas Luminiscentes/genética , Receptor de Insulina/genética , Recombinación Genética , Linfocitos T Reguladores/inmunología , Animales , Proteínas Bacterianas/biosíntesis , Linaje de la Célula , Cruzamientos Genéticos , Genes Reporteros , Genotipo , Integrasas/metabolismo , Proteínas Luminiscentes/biosíntesis , Ratones Noqueados , Ratones Transgénicos , Fenotipo , Reacción en Cadena de la Polimerasa/métodos , Regiones Promotoras Genéticas , Receptor de Insulina/deficiencia , Linfocitos T Reguladores/metabolismo
8.
J Sports Sci Med ; 18(4): 669-673, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31827351

RESUMEN

Regular physical activity and exercise interventions are suspected to have anti-inflammatory effects depending on exercise modality, thereby potentially reducing the risk and progress of several chronic diseases. Alterations in the kynurenine pathway may represent a link between inflammatory responses following acute exercise and chronic anti-inflammatory properties, such as increased levels of regulatory T-cells (Treg). Here, we hypothesize that acute exercise activates the kynurenine pathway and physical fitness is associated with proportions of circulating anti-inflammatory Treg in older healthy women. Nineteen older healthy female participants (55 years (SD: ± 5.6)) completed a cardiopulmonary incremental exercise test (CPET) with spirometry on a bicycle ergometer until exhaustion with maximum oxygen uptake (VO2max) as outcome. Blood samples were taken before (T0) and one minute after (T1) the CPET. Levels of tryptophan, serotonin and kynurenine were determined by enzyme-linked immunosorbent assays. Flow cytometry was used to identify proportions of T-cell subsets. Both, kynurenine (p = 0.003, d = 0.40) and the kynurenine/tryptophan ratio (p = 0.034, d = 0.48) increased significantly after acute exercise. Moreover, participants` VO2max was strongly correlated with Treg levels (p < 0.001, r = 0.689). This is the first study indicating a kynurenine pathway activation following acute exercise in older healthy women. The observed correlation between Treg levels and VO2max emphasizes a potential link between short-term upregulated kynurenine levels and longer-term anti-inflammatory properties of exercise. Future research is needed to clarify to what extend acute exercise-induced activations of the kynurenine pathway contribute to Treg differentiation.


Asunto(s)
Ejercicio/fisiología , Quinurenina/sangre , Linfocitos T Reguladores/metabolismo , Anciano , Biomarcadores/sangre , Índice de Masa Corporal , Diferenciación Celular , Femenino , Humanos , Consumo de Oxígeno/fisiología , Resistencia Física/fisiología , Aptitud Física/fisiología , Proyectos Piloto , Serotonina/sangre , Linfocitos T Reguladores/inmunología , Triptófano/sangre
9.
Int J Mol Sci ; 20(20)2019 Oct 19.
Artículo en Inglés | MEDLINE | ID: mdl-31635041

RESUMEN

Regular aerobic exercise, independently of weight loss, improves metabolic and anti-inflammatory states, and can be regarded as beneficial in counteracting obesity-induced low-grade inflammation. However, it is still unknown how exercise alters immunometabolism in a context of dietary changes. Agonists of the Peroxisome Proliferator Activated-Receptor beta/delta (PPARß/δ) have been studied this last decade as "exercise-mimetics", which are potential therapies for metabolic diseases. In this study, we address the question of whether PPARß/δ agonist treatment would improve the immunometabolic changes induced by exercise in diet-induced obese female mice, having switched from a high fat diet to a normal diet. 24 mice were assigned to groups according to an 8-week exercise training program and/or an 8-week treatment with 3 mg/kg/day of GW0742, a PPARß/δ agonist. Our results show metabolic changes of peripheral lymphoid tissues with PPARß/δ agonist (increase in fatty acid oxidation gene expression) or exercise (increase in AMPK activity) and a potentiating effect of the combination of both on the percentage of anti-inflammatory Foxp3+ T cells. Those effects are associated with a decreased visceral adipose tissue mass and skeletal muscle inflammation (TNF-α, Il-6, Il-1ß mRNA level), an increase in skeletal muscle oxidative capacities (citrate synthase activity, endurance capacity), and insulin sensitivity. We conclude that a therapeutic approach targeting the PPARß/δ pathway would improve obesity treatment.


Asunto(s)
Dieta Alta en Grasa , Metabolismo Energético , Obesidad/metabolismo , PPAR delta/agonistas , PPAR-beta/agonistas , Condicionamiento Físico Animal , Pérdida de Peso , Animales , Metabolismo Energético/efectos de los fármacos , Femenino , Glucosa/metabolismo , Resistencia a la Insulina , Metabolismo de los Lípidos , Recuento de Linfocitos , Ratones , Ratones Obesos , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Obesidad/etiología , Obesidad/terapia , PPAR delta/metabolismo , PPAR-beta/metabolismo , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Tiazoles/farmacología
10.
J Immunol Res ; 2019: 1820182, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31637264

RESUMEN

Objectives: To investigate CD4+CD25+FoxP3+ T regulatory cells (Tregs) in the peripheral blood of patients with atopic dermatitis (AD) and its correlation with disease severity. Methods: Blood samples from 79 AD patients before and after four-week conventional treatment were collected. Cell counts of CD4+CD25+FoxP3+Tregs, CD4+CD25+FoxP3-T effector cells (Teffs), and CD4+IL-10+Tregs were analyzed by flow cytometry. Serum levels of IL-4, IL-10, IL-12, IL-13, IFN-γ, and TGF-ß were measured by ELISA. Results: The pretreatment cell count of CD4+CD25+FoxP3+Tregs positively correlated with disease severity in all patients (P < 0.0001). However, when that correlation was rechecked based on the treatment response, a much stronger correlation of that was found in those patients with remission after treatment, while no correlation of that was found in patients without remission. Both the cell count and proportions of peripheral CD4+CD25+FoxP3+Tregs and CD4+CD25+FoxP3-Teffs reduced significantly after treatment in patients with remission, but remained unchanged in patients without remission. The cell count and proportion of CD4+IL-10+Tregs did not change after treatment in both groups. In patients with remission, serum levels of IL-4 and IL-13 significantly reduced (all P < 0.05); IL-12 and IFN-γ levels increased significantly (all P < 0.05); IL-10 and TGF-ß levels remained unchanged after treatment. None of those cytokine levels changed in patients without remission. Conclusions: CD4+CD25+FoxP3+Tregs is associated with AD development and severity in some patients but not in others. AD maybe divided into CD4+CD25+FoxP3+Treg-associated subtype, which CD4+CD25+FoxP3+Treg is parallel to the activity of AD, and nonassociated subtype, which CD4+CD25+FoxP3+Treg is not related. This subgroup difference may contribute partly to the nonidentical markers that have been found in AD and should be studied further.


Asunto(s)
Citocinas/sangre , Dermatitis Atópica/inmunología , Factores de Transcripción Forkhead/sangre , Linfocitos T Reguladores/metabolismo , Adulto , Recuento de Células , Dermatitis Atópica/tratamiento farmacológico , Femenino , Antagonistas de los Receptores Histamínicos/uso terapéutico , Humanos , Masculino , Índice de Severidad de la Enfermedad , Adulto Joven
11.
Int J Mol Sci ; 20(19)2019 Sep 28.
Artículo en Inglés | MEDLINE | ID: mdl-31569411

RESUMEN

In central lymphoid tissues, mature lymphocytes are generated and pathogenic autoreactive lymphocytes are deleted. However, it is currently known that a significant number of potentially pathogenic autoreactive lymphocytes escape the deletion and populate peripheral lymphoid tissues. Therefore, peripheral mechanisms are present to prevent these potentially pathogenic autoreactive lymphocytes from harming one's own tissues. One such mechanism is dictated by regulatory T (Treg) cells. So far, the most extensively studied Treg cells are CD4+Foxp3+ Treg cells. However, recent clinical trials for the treatment of immune-mediated diseases using CD4+ Foxp3+ Treg cells met with limited success. Accordingly, it is necessary to explore the potential importance of other Treg cells such as CD8+ Treg cells. In this regard, one extensively studied CD8+ Treg cell subset is Qa-1(HLA-E in human)-restricted CD8+ Treg cells, in which Qa-1(HLA-E) molecules belong to a group of non-classical major histocompatibility complex Ib molecules. This review will first summarize the evidence for the presence of Qa-1-restricted CD8+ Treg cells and their regulatory mechanisms. Major discussions will then focus on the potential clinical translation of Qa-1-restricted CD8+ Treg cells. At the end, we will briefly discuss the current status of human studies on HLA-E-restricted CD8+ Treg cells as well as potential future directions.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Linfocitos T Reguladores/inmunología , Investigación en Medicina Traslacional , Animales , Linfocitos T CD8-positivos/metabolismo , Epítopos/inmunología , Humanos , Enfermedades del Sistema Inmune/etiología , Enfermedades del Sistema Inmune/metabolismo , Enfermedades del Sistema Inmune/terapia , Inmunomodulación , Péptidos/inmunología , Linfocitos T Reguladores/metabolismo , Vacunación
12.
Nutr Metab Cardiovasc Dis ; 29(11): 1254-1260, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31585776

RESUMEN

BACKGROUND AND AIM: Regulatory T cells (Tregs) play an important role in cardiovascular complications with the immune response. However, the role of Tregs in high fat diet (HFD)-induced myocardial fibrosis has not been fully elucidated to date. Therefore, we investigated whether HFD suppresses Tregs activation in the myocardium of spontaneously hypertensive rats (SHRs), which aggregates myocardial fibrosis. METHODS AND RESULTS: Eight-week-old male SHRs were fed to either HFD or control diet (CHO) groups for 12 weeks. We measured Tregs (CD4+FoxP3+) in the heart and mediastinal lymph nodes (LNs). The flow cytometry analysis confirmed that SHR-HFD exhibited a decreased Tregs compared to that of SHR-CHO in the heart and mediastinal LNs. Furthermore, the CD4 and FoxP3 antigens were used in the immunofluorescence microscopy of Tregs in the heart tissues. In the heart, dual staining for the Treg population was increased more in SHR-CHO than it was in SHR-HFD rats. In line with these findings, SHR-HFD significantly exacerbated myocardial fibrosis. CONCLUSION: We found that diet-induced obesity typically showed an exacerbated myocardial fibrosis and down-regulation of Tregs pathway in the heart and mediastinal LNs. Therefore, we suggest that the up-regulation of Tregs may be a promising therapeutic approach to preventing obesity induced heart failure.


Asunto(s)
Cardiomiopatías/inmunología , Dieta Alta en Grasa , Miocardio/inmunología , Obesidad/inmunología , Linfocitos T Reguladores/inmunología , Animales , Biomarcadores/metabolismo , Cardiomiopatías/metabolismo , Cardiomiopatías/patología , Modelos Animales de Enfermedad , Regulación hacia Abajo , Fibrosis , Factores de Transcripción Forkhead/inmunología , Factores de Transcripción Forkhead/metabolismo , Ganglios Linfáticos/inmunología , Masculino , Mediastino , Miocardio/metabolismo , Miocardio/patología , Obesidad/metabolismo , Obesidad/patología , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Linfocitos T Reguladores/metabolismo
13.
Anticancer Res ; 39(10): 5369-5374, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31570431

RESUMEN

BACKGROUND/AIM: Cytokine-induced killer (CIK) cells are ex vivo expanded major histocompatibility complex (MHC)-unrestricted cytotoxic cells with promising effects against a variety of cancer types. Regulatory T-cells (T-reg) have been shown to reduce the effectiveness of CIK cells against tumor cells. Peptide P60 has been shown to inhibit the immunosuppressive functions of T-regs. This study aimed at examining the effect of p60 on CIK cells efficacy against renal and pancreatic cancer cells. MATERIALS AND METHODS: The effect of P60 on CIK cytotoxicity was examined using flow cytometry, WST-8-based cell viability assay and interferon γ (IFNγ) ELISA. RESULTS: P60 treatment resulted in a significant decrease in the viability of renal and pancreatic cancer cell lines co-cultured with CIK cells. No increase in IFNγ secretion from CIK cells was detected following treatment with P60. P60 caused no changes in the distribution of major effector cell populations in CIK cell cultures. CONCLUSION: P60 may potentiate CIK cell cytotoxicity against tumor cells.


Asunto(s)
Células Asesinas Inducidas por Citocinas/efectos de los fármacos , Citocinas/metabolismo , Factores de Transcripción Forkhead/antagonistas & inhibidores , Neoplasias Renales/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Péptidos/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Técnicas de Cocultivo/métodos , Células Asesinas Inducidas por Citocinas/metabolismo , Citotoxicidad Inmunológica/efectos de los fármacos , Humanos , Interferón gamma/metabolismo , Riñón/efectos de los fármacos , Riñón/metabolismo , Neoplasias Renales/metabolismo , Páncreas/efectos de los fármacos , Páncreas/metabolismo , Neoplasias Pancreáticas/metabolismo , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/metabolismo
14.
Nat Commun ; 10(1): 4601, 2019 10 10.
Artículo en Inglés | MEDLINE | ID: mdl-31601798

RESUMEN

During pregnancy, trophoblast cells sustain the maternal-fetal tolerance via expressing and secreting various chemokines and cytokines. Our previous study revealed the expression of interleukin-35 (IL-35) in human first-trimester trophoblasts. Here we show that IL-35 is expressed in both human first-trimester primary trophoblast cells and a trophoblast cell line. Trophoblast cells inhibit the proliferation of human naive conventional T cells (Tconv cells) and convert suppressed Tconv cells into iTR35 in an IL-35-dependent manner. Mechanistically, trophoblast cell derived IL-35 mediates its function through phosphorylation of STAT1 and STAT3. In vivo studies confirm that mice with immunologically spontaneous abortion have lower levels of IL-35 and iTR35 cells at the maternal-fetal interface, and neutralizing anti-IL-35 mAb enhances abortion rates. Meanwhile, exogenous IL-35 induces iTR35 and prevents immunological abortion. Our findings thus suggest that trophoblast cells have a critical function in preserving maternal-fetal tolerance via secreting IL-35 during pregnancy.


Asunto(s)
Interleucinas/metabolismo , Intercambio Materno-Fetal/fisiología , Linfocitos T Reguladores/inmunología , Trofoblastos/citología , Animales , Proliferación Celular , Femenino , Humanos , Tolerancia Inmunológica , Interleucinas/sangre , Interleucinas/inmunología , Interleucinas/farmacología , Masculino , Intercambio Materno-Fetal/inmunología , Ratones Endogámicos BALB C , Ratones Endogámicos DBA , Placenta/citología , Placenta/inmunología , Embarazo , Proteínas Recombinantes/genética , Proteínas Recombinantes/inmunología , Proteínas Recombinantes/farmacología , Linfocitos T/citología , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T Reguladores/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Trofoblastos/inmunología , Trofoblastos/metabolismo
15.
DNA Cell Biol ; 38(11): 1387-1401, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31549881

RESUMEN

Immune cell infiltration is associated with the prognosis of cancer. This study focused on the immune infiltration profiling and their association with survival outcome in nonsmall cell lung cancer (NSCLC). Research data were obtained from the Gene Expression Omnibus and The Cancer Genome Atlas databases. CIBERSORT algorithm was applied to assess the relative proportions of 22 kinds of immune cells. Log-rank test was performed to compare the survival outcome of patients with different proportions of immune cells. The estimated hazard ratios were presented with forest plot. Multivariate Cox regression analysis was conducted to estimate the adjusted associations between different types of infiltrating immune cells and survival prognosis controlling for other clinical features and confounders. With the CIBERSORT approach, we assessed the proportions of 22 infiltrating immune cells of 2050 cases with NSCLC. By conducting survival analysis, we found different survival outcomes among cases with different proportions of certain types of infiltrating immune cells. Among the cell subsets investigated, plasma cells (hazard ratio [HR] = 0.775, 95% confidence interval [CI]: 0.669-0.898) and regulatory T cells (HR = 1.258, 95% CI: 1.091-1.451) were associated with survival outcome of NSCLC patients controlling for other covariates. Subgroup analysis suggested a good consistency and robustness of our results. Our findings might provide useful information for prognosis prediction and cellular study in NSCLC.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Linfocitos Infiltrantes de Tumor/metabolismo , Transcriptoma , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Células Plasmáticas/metabolismo , Pronóstico , Análisis de Supervivencia , Linfocitos T Reguladores/metabolismo
16.
Gastroenterology ; 157(6): 1584-1598, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31513797

RESUMEN

BACKGROUND & AIMS: T-regulatory (Treg) cells suppress the immune response to maintain homeostasis. There are 2 main subsets of Treg cells: FOXP3 (forkhead box protein 3)-positive Treg cells, which do not produce high levels of effector cytokines, and type 1 Treg (Tr1) cells, which are FOXP3-negative and secrete interleukin (IL) 10. IL10 is an anti-inflammatory cytokine, so Tr1 cells might be used in the treatment of inflammatory bowel diseases. We aimed to develop methods to isolate and expand human Tr1 cells and define their functions. METHODS: We obtained blood and colon biopsy samples from patients with Crohn's disease or ulcerative colitis or healthy individuals (controls). CD4+ T cells were isolated from blood samples and stimulated with anti-CD3 and anti-CD28 beads, and Tr1 cells were purified by using an IL10 cytokine-capture assay and cell sorting. FOXP3-positive Treg cells were sorted as CD4+CD25highCD127low cells from unstimulated cells. Tr1 and FOXP3-positive Treg cells were expanded, and phenotypes and gene expression profiles were compared. T cells in peripheral blood mononuclear cells from healthy donors were stimulated with anti-CD3 and anti-CD28 beads, and the suppressive abilities of Tr1 and FOXP3-positive Treg cells were measured. Human colon organoid cultures were established, cultured with supernatants from Tr1 or FOXP3-positive cells, and analyzed by immunofluorescence and flow cytometry. T84 cells (human colon adenocarcinoma epithelial cells) were incubated with supernatants from Tr1 or FOXP3-positive cells, and transepithelial electrical resistance was measured to determine epithelial cell barrier function. RESULTS: Phenotypes of Tr1 cells isolated from control individuals vs patients with Crohn's disease or ulcerative colitis did not differ significantly after expansion. Tr1 cells and FOXP3-positive Treg cells suppressed proliferation of effector T cells, but only Tr1 cells suppressed secretion of IL1B and tumor necrosis factor from myeloid cells. Tr1 cells, but not FOXP3-positive Treg cells, isolated from healthy individuals and patients with Crohn's disease or ulcerative colitis secreted IL22, which promoted barrier function of human intestinal epithelial cells. Tr1 cell culture supernatants promoted differentiation of mucin-producing goblet cells in intestinal organoid cultures. CONCLUSIONS: Human Tr1 cells suppress proliferation of effector T cells (adaptive immune response) and production of IL1B and TNF by myeloid cells (inmate immune response). They also secrete IL22 to promote barrier function. They might be developed as a cell-based therapy for intestinal inflammatory disorders.


Asunto(s)
Colitis Ulcerosa/inmunología , Enfermedad de Crohn/inmunología , Interleucina-10/metabolismo , Mucosa Intestinal/patología , Linfocitos T Reguladores/inmunología , Adulto , Anciano , Biopsia , Comunicación Celular/inmunología , Proliferación Celular , Células Cultivadas , Colitis Ulcerosa/sangre , Colitis Ulcerosa/terapia , Colon/citología , Colon/inmunología , Colon/patología , Enfermedad de Crohn/sangre , Enfermedad de Crohn/terapia , Femenino , Factores de Transcripción Forkhead/inmunología , Factores de Transcripción Forkhead/metabolismo , Voluntarios Sanos , Humanos , Interleucina-10/inmunología , Interleucinas/inmunología , Interleucinas/metabolismo , Mucosa Intestinal/citología , Mucosa Intestinal/inmunología , Masculino , Persona de Mediana Edad , Cultivo Primario de Células , Linfocitos T Citotóxicos/inmunología , Linfocitos T Reguladores/metabolismo , Linfocitos T Reguladores/trasplante
17.
Toxicol Lett ; 316: 27-34, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31513887

RESUMEN

OBJECTIVE: Atherosclerosis is an autoimmune inflammatory disease that is closely associated with long-term exposure to fine particulate matter (PM2.5). CD4+CD25+Foxp3+ regulatory T cells (Tregs) play a critical role in the regulation of T cell-mediated immune responses, and the depletion of CD4+CD25+Foxp3+ Tregs has been thought to play a prominent role in atherosclerosis. Therefore, we investigated the association between the CD4+CD25+Foxp3+ Tregs population and atherosclerotic development in ApoE-/- mice exposed to PM2.5. METHODS: We employed a real-world system to subject 40 ApoE-/- mice to ambient inhalation of PM2.5 (PM2.5 group, n = 20) or filtered air (FA group, n = 20) for 12 weeks. PM2.5 source apportionment, atherosclerotic lesions within aorta, lipid deposition and plaque accumulation in whole artery, serum level of inflammatory factors and lipid profiles, CD4+CD25+Foxp3+ Tregs population in splenocytes, Foxp3 protein and mRNA expressions in descending aorta and spleen were quantified, respectively. RESULTS: The daily average concentration of PM2.5 was 57.4 ± 25.6 µg/m3. Atherosclerotic lesions within aorta, lipid deposition and plaque accumulation in whole artery, serum levels of IL-6, TNF-α, TC and LDL-C in the PM2.5 group increased significantly compared to the FA group. Whereas, serum levels of IL-10 and TGF-ß, CD4+CD25+Foxp3+ Tregs population in splenocytes, Foxp3 protein and mRNA expressions in descending aorta and spleen in the PM2.5 group decreased significantly compared to the FA group. CONCLUSION: These results suggest that PM2.5 could accelerate the development of atherosclerosis in ApoE-/- mice, which is related to CD4+CD25+Foxp3+ Tregs down-regulation, as well as lipid deposition and systemic inflammation.


Asunto(s)
Aorta/efectos de los fármacos , Enfermedades de la Aorta/inducido químicamente , Aterosclerosis/inducido químicamente , Factores de Transcripción Forkhead/metabolismo , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Material Particulado/toxicidad , Linfocitos T Reguladores/efectos de los fármacos , Animales , Aorta/inmunología , Aorta/metabolismo , Aorta/patología , Enfermedades de la Aorta/sangre , Enfermedades de la Aorta/inmunología , Enfermedades de la Aorta/patología , Aterosclerosis/sangre , Aterosclerosis/inmunología , Aterosclerosis/patología , Biomarcadores/sangre , LDL-Colesterol/sangre , Citocinas/sangre , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Factores de Transcripción Forkhead/inmunología , Predisposición Genética a la Enfermedad , Mediadores de Inflamación/sangre , Subunidad alfa del Receptor de Interleucina-2/inmunología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados para ApoE , Tamaño de la Partícula , Fenotipo , Placa Aterosclerótica , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Linfocitos T Reguladores/patología , Factores de Tiempo
18.
Iran J Allergy Asthma Immunol ; 18(4): 369-378, 2019 Aug 17.
Artículo en Inglés | MEDLINE | ID: mdl-31522445

RESUMEN

Interleukin (IL)-4-producing-CD8 (cytotoxic T cells, Tc) contribute to lung eosinophilia and airway hyper-responsiveness (AHR) to an antigen. CD4+CD25+ regulatory T cells (Tregs) attenuate airway inflammation and AHR. This study investigated whether Tregs decrease Tc2frequencies in ovalbumin (OVA)-induced asthma model of mice. Female C57BL/6 mice were sensitized with OVA intraperitoneally and challenged with OVA intranasally to induce allergic asthma model. Tregs were sorted by fluorescence activated cell sorting (FACS) and magnetic activated cell sorting (MACS) microbeads. OVA-sensitized mice were injected with Tregs or phosphate buffer saline (PBS) by tail vein ahead of the first challenge. Airway inflammation and airway hyper-responsiveness (AHR)were evaluated by histological analysis and invasive method, respectively. OVA-specific IgE and cytokine levels were detected by ELISA. Flow cytometry was used to detect the percentages of Tc1 and Tc2. Gata3 and T-bet mRNA was determined by quantitative PCR (qPCR). OVA-sensitized and challenged mice displayed typical asthma features, which included eosinophilic airway inflammation, higher levels of Th2 cytokines and AHR. Gata3 mRNA, Tc2 frequencies and OVA-specific IgE levels were significantly increased in OVA-sensitized and challenged mice. Compared to PBS treatment, Tregs decreased Tc2 frequencies, airway inflammation, Th2 cytokine levels and AHR in OVA-sensitized and challenged mice. IL-13 levels were negatively correlated with Tc1 frequencies and with IFNg levels in experimental mice. Our results demonstrated that Tregs could prevent airway inflammation and AHR by decreasing Tc2 frequencies and cytokine levels in OVA-induced asthma model of mice, supporting Tregmight be as a potent therapeutic target for alleviating airway inflammation and AHR.


Asunto(s)
Asma/inmunología , Linfocitos T CD8-positivos/inmunología , Comunicación Celular/inmunología , Linfocitos T Reguladores/inmunología , Alérgenos/inmunología , Animales , Asma/metabolismo , Biomarcadores , Antígenos CD4/metabolismo , Linfocitos T CD8-positivos/metabolismo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , Inmunofenotipificación , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Interleucina-4/metabolismo , Recuento de Linfocitos , Ratones , Hipersensibilidad Respiratoria/inmunología , Hipersensibilidad Respiratoria/metabolismo , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Linfocitos T Reguladores/metabolismo
19.
Mol Med Rep ; 20(5): 4303-4314, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31545427

RESUMEN

Inducible regulatory T cells (iTregs) are an important subset of Tregs and play a role in the maintenance of peripheral tolerance, and the occurrence of a number of diseases, including tumors and autoimmune diseases. However, the instability of iTregs is a major obstacle for their potential application in clinical trials. The underlying mechanism of iTreg instability remains largely unknown. In the present study, the expression level of microRNA (miRNA/miR)­30a in murine iTregs was evaluated using reverse transcription­quantitative PCR. miR­30a mimics and a miR­negative control (NC) were transiently transfected into iTregs using Nucleofector technology. The effects of miR­30a on the suppressive function of murine iTregs in vitro and in vivo were investigated using MTT, adoptive cell transfer (ACT) and flow cytometry assays, as well as a murine model of lung cancer. In the present study, it was identified that the expression level of miR­30a was lower in murine iTregs in vitro compared with natural (n)Tregs. Furthermore, compared with miR­NC, miR­30a mimics impaired the suppressive function of murine iTregs on murine CD4+ T cell proliferation in vitro, which was accompanied by the altered expression of cytotoxic T lymphocyte­associated antigen 4 and glucocorticoid induced tumor necrosis factor receptor, as well as transforming growth factor­ß and interleukin­10. It was also observed that, compared with miR­NC, miR­30a mimics abrogated the suppressive effects of murine iTregs on murine CD8+ T cell function in vivo, producing an effective antitumor effect in mice bearing 3LL lung cancer cells in the ACT assay. From a mechanistic point, the expression level of suppressor of cytokine signaling 1, a putative target of miR­30a, was elevated, altering the activation of the Akt and STAT1 pathway in the miR­30a mimic transfected group compared with the miR­NC group, reducing the suppressive function of murine iTregs. The present study identified a role for miR­30a in the instability of iTregs and provided a novel insight into the development of therapeutic strategies for promoting T­cell immunity via the regulation of iTreg instability by targeting specific miRNAs.


Asunto(s)
Regulación de la Expresión Génica , Activación de Linfocitos/genética , MicroARNs/genética , Interferencia de ARN , Proteína 1 Supresora de la Señalización de Citocinas/genética , Linfocitos T Reguladores/metabolismo , Animales , Biomarcadores , Diferenciación Celular , Femenino , Granzimas/metabolismo , Inmunofenotipificación , Interferón gamma/metabolismo , Ratones , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/inmunología
20.
BMC Immunol ; 20(1): 32, 2019 09 04.
Artículo en Inglés | MEDLINE | ID: mdl-31484501

RESUMEN

BACKGROUND: The development of Systemic lupus erythematosus (SLE) has been associated with the balance of Th17 and Treg cells. IL-2 and rapamycin can influence the populations of both Th17 and Treg cells. However, it is unclear whether low dose of IL-2 and rapamycin can relieve the symptoms of SLE patients and what is the mechanisms. In this study, we aim to analyze the effect of low dose of IL-2 plus rapamycin on the number of Tregs, Th17 cells and the ratio of Th17/Treg cells, as well as to evaluate its therapeutic efficacy in refractory SLE patients. RESULT: Fifty refractory SLE patients and 70 healthy controls were enrolled and followed up for 24 weeks. We found that compared with HC, the refractory SLE patients had a lower number of Tregs, a similar number of Th17 cells, but an increased ratio of Th17/Treg. After the treatment, the number of Tregs of the patients at 12th and 24th week was significantly increased. While the number of Th17 cells was unchanged, the ratio of Th17/Treg was significantly decreased at both 6 weeks and 24 weeks. After 6, 12 and 24 weeks of treatment, the SLEDAI score was significantly reduced. The prednison dosage at 6th,12th and 24th week post treatment was significantly decreased. CONCLUSION: Our results support that the reduction of Tregs and the imbalance of Th17/Treg cells were correlated with the occurrence and development of refractory SLE. Low dose of IL-2 combined with rapamycin was able to restore the number of Tregs and the balance of Th17/Treg cells. As a result, this approach was able to induce immune tolerance and promote disease remission, allowing for the reduction in prednisone dosage. TRIAL REGISTRATION: ChiCTR-IPR-16009451 Registration date: 2016/10/16.


Asunto(s)
Interleucina-2/farmacología , Lupus Eritematoso Sistémico/inmunología , Sirolimus/farmacología , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Células Th17/efectos de los fármacos , Células Th17/inmunología , Adulto , Biomarcadores , Sinergismo Farmacológico , Quimioterapia Combinada , Femenino , Humanos , Interleucina-2/administración & dosificación , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Lupus Eritematoso Sistémico/metabolismo , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Sirolimus/administración & dosificación , Subgrupos de Linfocitos T/efectos de los fármacos , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Linfocitos T Reguladores/metabolismo , Células Th17/metabolismo , Resultado del Tratamiento
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA