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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.
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
4.
Cancer Sci ; 111(3): 795-806, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31883400

RESUMEN

Esophageal cancer is currently one of the most fatal cancers. However, there is no effective treatment. Increasing evidence suggests that interleukin (IL)-33 has a significant role in tumor progression and metastasis. Currently, the underlying cellular and molecular mechanism of IL-33 in promoting esophageal squamous cell carcinoma (ESCC) remains unclear. In this study, we investigated whether IL-33 could induce the epithelial-mesenchymal transition (EMT) in ESCC. Interleukin-33 expression was examined in ESCC and corresponding adjacent normal tissues by immunohistochemistry and quantitative real-time PCR experiments. Elevated IL-33 levels were observed in ESCC tissues. Further in vitro experiments were undertaken to elucidate the effect of IL-33 on migration and invasion in KYSE-450 and Eca-109 esophageal cancer cells. Knockdown of IL-33 decreased the metastasis and invasion capacity in esophageal cancer cells, whereas IL-33 overexpression showed the opposite effect. We then screened CCL2 which is a downstream molecule of IL-33, and proved that IL-33 could promote tumor development and metastasis by recruiting regulatory T cells (Tregs) through CCL2, and IL-33 regulated the expression of CCL2 through transforming growth factor-ß in Treg cells. Knockdown of IL-33 decreased the development of human ESCC xenografts in BALB/c nude mice. Collectively, we found that the IL-33/nuclear factor-κB/CCL2 pathway played an essential role in human ESCC progress. Hence, IL-33 should be considered as an effective therapy target for ESCC.


Asunto(s)
Quimiocina CCL2/genética , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas de Esófago/genética , Interleucina-33/genética , FN-kappa B/genética , Transducción de Señal/genética , Linfocitos T Reguladores/patología , Animales , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Progresión de la Enfermedad , Transición Epitelial-Mesenquimal/genética , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/patología , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos
5.
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
6.
Int J Mol Sci ; 20(18)2019 Sep 19.
Artículo en Inglés | MEDLINE | ID: mdl-31546958

RESUMEN

Shellfish allergy is one of the most common food allergies, with tropomyosin as the major cross-reactive allergen. However, no allergen-specific immunotherapy is clinically available. Recently, we designed two shrimp hypoallergens MEM49 and MED171. This study aimed to examine and compare the efficacy of the MEM49- and MED171-based DNA vaccines (pMEM49 and pMED171) in modulating shrimp allergy in a murine model of shrimp tropomyosin sensitivity. Intradermal immunization of BALB/c mice with pMEM49 or pMED171 effectively down-modulated allergic symptoms, tropomyosin-specific IgE levels, intestinal Th2 cytokines expression, and inflammatory cell infiltration. Both pMEM49 and pMED171 increased the frequency of regulatory T cells, but to a greater extent by pMED171 with upregulation of gut-homing molecules integrin-α4ß7. The functionality of the pMED171-induced Treg cells was further illustrated by anti-CD25-mediated depletion of Treg cells and the adoptive transfer of CD4+CD25+Foxp3+Treg cells. Collectively, the data demonstrate that intradermal administration of pMED171 leads to the priming, activation, and migration of dermal dendritic cells which subsequently induce Treg cells, both locally and systemically, to downregulate the allergic responses to tropomyosin. This study is the first to demonstrate the potency of hypoallergen-encoding DNA vaccines as a therapeutic strategy for human shellfish allergy via the vigorous induction of functional Treg cells.


Asunto(s)
Alérgenos , Proteínas de Artrópodos , Penaeidae , Hipersensibilidad a los Mariscos , Linfocitos T Reguladores , Tropomiosina , Vacunas de ADN , Alérgenos/genética , Alérgenos/inmunología , Animales , Proteínas de Artrópodos/genética , Proteínas de Artrópodos/inmunología , Ratones , Ratones Endogámicos BALB C , Penaeidae/genética , Penaeidae/inmunología , Hipersensibilidad a los Mariscos/genética , Hipersensibilidad a los Mariscos/inmunología , Hipersensibilidad a los Mariscos/patología , Hipersensibilidad a los Mariscos/terapia , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/patología , Células Th2/inmunología , Células Th2/patología , Tropomiosina/genética , Tropomiosina/inmunología , Vacunas de ADN/genética , Vacunas de ADN/inmunología
7.
Int J Mol Sci ; 20(19)2019 Sep 23.
Artículo en Inglés | MEDLINE | ID: mdl-31547627

RESUMEN

The tumor bulk is composed of a highly heterogeneous population of cancer cells, as well as a large variety of resident and infiltrating host cells, extracellular matrix proteins, and secreted proteins, collectively known as the tumor microenvironment (TME). The TME is essential for driving tumor development by promoting cancer cell survival, migration, metastasis, chemoresistance, and the ability to evade the immune system responses. Therapeutically targeting tumor-associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), regulatory T-cells (T-regs), and mesenchymal stromal/stem cells (MSCs) is likely to have an impact in cancer treatment. In this review, we focus on describing the normal physiological functions of each of these cell types and their behavior in the cancer setting. Relying on the specific surface markers and secreted molecules in this context, we review the potential targeting of these cells inducing their depletion, reprogramming, or differentiation, or inhibiting their pro-tumor functions or recruitment. Different approaches were developed for this targeting, namely, immunotherapies, vaccines, small interfering RNA, or small molecules.


Asunto(s)
Inmunoterapia , Neoplasias , Microambiente Tumoral/inmunología , Fibroblastos Asociados al Cáncer/inmunología , Fibroblastos Asociados al Cáncer/patología , Diferenciación Celular/inmunología , Humanos , Células Madre Mesenquimatosas/inmunología , Células Madre Mesenquimatosas/patología , Neoplasias/inmunología , Neoplasias/patología , Neoplasias/terapia , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/patología
8.
Mol Med Rep ; 20(4): 3617-3624, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31485649

RESUMEN

It has been reported that loss and degradation of epidermal melanocytes is closely associated with the pathogenesis of vitiligo. In addition, CD8+ T and regulatory T (Treg) cells serve an important role during these two processes. MicroRNA­155 (miR­155) is known to contribute to the pathogenesis of vitiligo; however, the mechanism by which miR­155 regulates the development of vitiligo remains unclear. In the present study, naïve T and CD8+ T cells were isolated from a patient with non­segmental vitiligo by flow cytometry. The cells were differentiated into Treg cells by treatment with interleukin­2, transforming growth factor­ß and retinoic acid. In addition, miR­155 agonists and antagonists were used to investigate the effect of miR­155 on the proliferation of CD8+ T cells, Treg cells and melanocytes. The results demonstrated that the miR­155 agonist significantly decreased the rate of CD8+ T cell growth, as well as promoted the proliferation of melanocytes by inducing an increase in the percentage of Treg cells. By contrast, the miR­155 antagonist inhibited the proliferation of melanocytes by decreasing the percentage of Treg cells. miR­155 protected melanocyte survival by increasing the number of Treg cells and by decreasing the number of CD8+ T cells. Therefore, these data may provide a new prospect for the treatment of vitiligo.


Asunto(s)
Linfocitos T CD8-positivos/patología , MicroARNs/genética , Linfocitos T Reguladores/patología , Vitíligo/genética , Adulto , Linfocitos T CD8-positivos/citología , Diferenciación Celular , Proliferación Celular , Supervivencia Celular , Células Cultivadas , Humanos , Masculino , Melanocitos/citología , Melanocitos/patología , Persona de Mediana Edad , Linfocitos T Reguladores/citología , Vitíligo/patología
9.
J Neuroinflammation ; 16(1): 163, 2019 Aug 05.
Artículo en Inglés | MEDLINE | ID: mdl-31383034

RESUMEN

BACKGROUND: Traumatic brain injury (TBI) is a major cause of death and disability. T cells were shown to infiltrate the brain during the first days after injury and to exacerbate tissue damage. The objective of this study was to investigate the hitherto unresolved role of immunosuppressive, regulatory T cells (Tregs) in experimental TBI. METHODS: "Depletion of regulatory T cell" (DEREG) and wild type (WT) C57Bl/6 mice, treated with diphtheria toxin (DTx) to deplete Tregs or to serve as control, were subjected to the controlled cortical impact (CCI) model of TBI. Neurological and motor deficits were examined until 5 days post-injury (dpi). At the 5 dpi endpoint, (immuno-) histological, protein, and gene expression analyses were carried out to evaluate the consequences of Tregs depletion. Comparison of parametric or non-parametric data between two groups was done using Student's t test or the Mann-Whitney U test. For multiple comparisons, p values were calculated by one-way or two-way ANOVA followed by specific post hoc tests. RESULTS: The overall neurological outcome at 5 dpi was not different between DEREG and WT mice but more severe motor deficits occurred transiently at 1 dpi in DEREG mice. DEREG and WT mice did not differ in the extent of brain damage, blood-brain barrier (BBB) disruption, or neuronal excitotoxicity, as examined by lesion volumetry, immunoglobulin G (IgG) extravasation, or calpain-generated αII-spectrin breakdown products (SBDPs), respectively. In contrast, increased protein levels of glial fibrillary acidic protein (GFAP) and GFAP+ astrocytes in the ipsilesional brain tissue indicated exaggerated reactive astrogliosis in DEREG mice. T cell counts following anti-CD3 immunohistochemistry and gene expression analyses of Cd247 (CD3 subunit zeta) and Cd8a (CD8a) further indicated an increased number of T cells infiltrating the brain injury sites of DEREG mice compared to WT. These changes coincided with increased gene expression of pro-inflammatory interferon-γ (Ifng) in DEREG mice compared to WT in the injured brain. CONCLUSIONS: The results show that the depletion of Tregs attenuates T cell brain infiltration, reactive astrogliosis, interferon-γ gene expression, and transiently motor deficits in murine acute traumatic brain injury.


Asunto(s)
Astrocitos/patología , Lesiones Traumáticas del Encéfalo/patología , Encéfalo/patología , Gliosis/patología , Interferón gamma/genética , Depleción Linfocítica , Linfocitos T Reguladores/patología , Animales , Astrocitos/inmunología , Encéfalo/inmunología , Lesiones Traumáticas del Encéfalo/genética , Lesiones Traumáticas del Encéfalo/inmunología , Modelos Animales de Enfermedad , Gliosis/genética , Gliosis/inmunología , Inflamación/genética , Inflamación/inmunología , Inflamación/patología , Ratones , Linfocitos T Reguladores/inmunología
10.
Blood ; 134(17): 1406-1414, 2019 10 24.
Artículo en Inglés | MEDLINE | ID: mdl-31467059

RESUMEN

Immune checkpoint inhibitors are a powerful new tool in the treatment of cancer, with prolonged responses in multiple diseases, including hematologic malignancies, such as Hodgkin lymphoma. However, in a recent report, we demonstrated that the PD-1 inhibitor nivolumab led to rapid progression in patients with adult T-cell leukemia/lymphoma (ATLL) (NCT02631746). We obtained primary cells from these patients to determine the cause of this hyperprogression. Analyses of clonality, somatic mutations, and gene expression in the malignant cells confirmed the report of rapid clonal expansion after PD-1 blockade in these patients, revealed a previously unappreciated origin of these malignant cells, identified a novel connection between ATLL cells and tumor-resident regulatory T cells (Tregs), and exposed a tumor-suppressive role for PD-1 in ATLL. Identifying the mechanisms driving this alarming outcome in nivolumab-treated ATLL may be broadly informative for the growing problem of rapid progression with immune checkpoint therapies.


Asunto(s)
Antineoplásicos Inmunológicos/uso terapéutico , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Nivolumab/uso terapéutico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Linfocitos T Reguladores/patología , Adulto , Animales , Progresión de la Enfermedad , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Humanos , Leucemia-Linfoma de Células T del Adulto/genética , Leucemia-Linfoma de Células T del Adulto/patología , Ratones , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/metabolismo , Células Tumorales Cultivadas
11.
Prostate ; 79(14): 1658-1665, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31390096

RESUMEN

BACKGROUND: Regulatory T cells (Tregs) play important roles in the suppression of immune responses, including antitumor immune responses. C-C chemokine receptor 4 (CCR4) is highly expressed on effector Tregs, and anti-CCR4 antibody is attracting attention as a novel immunotherapeutic agent for solid tumors. This study aimed to evaluate the expression of CCR4-positive Tregs (CCR4+Tregs) in prostate cancer and estimate the clinical potential of CCR4-targeting therapy for prostate cancer. METHODS: A total of 15 radical prostatectomy (RP) specimens and 60 biopsy specimens from individuals diagnosed with prostate cancer were analyzed to evaluate the infiltration of CCR4+Tregs in prostate cancer. The relationships between the number of CCR4+Tregs and clinical parameters were investigated in RP and biopsy specimens. Moreover, the total number of Tregs, CCR4+Tregs, and T cells and the ratio of CCR4+Tregs to Tregs and T cells in biopsy specimens were compared between patients with poor prognosis who progressed to castration-resistant prostate cancer (CRPC) within 12 months (n = 13) and those with good prognosis who were stable with hormone-sensitive prostate cancer over 12 months (n = 47). Furthermore, biopsy specimens were divided into two groups: low and high CCR4+Treg expression groups and the prognosis was compared between them. RESULTS: There was a higher expression of CCR4+Tregs in RP specimens with a higher (≥8) Gleason score than in those with a lower (<8) Gleason score (P = .041). In biopsy specimens, 65.9% Tregs were positive for CCR4. The number of CCR4+Tregs positively correlated with clinical stage (P < .001) and Gleason score (P = .006). The total number of Tregs and CCR4+Tregs significantly increased in the poor prognosis group compared with that in the good prognosis group (P = .024 and .01, respectively). Furthermore, patients with lower CCR4+Treg expression levels showed a significantly longer time to progression to CRPC (not reached vs 27.3 months; P < .001) and median survival time (not reached vs 69.0 months; P = .014) than those with higher expression levels. CONCLUSIONS: CCR4+Tregs are highly infiltrated in the prostate tissue of patients with poor prognosis with potential to progress to CRPC. Furthermore, the degree of infiltration of CCR4+Tregs is related to the prognosis of prostate cancer.


Asunto(s)
Neoplasias de la Próstata/patología , Receptores CCR4/análisis , Linfocitos T Reguladores/química , Linfocitos T Reguladores/patología , Anciano , Biopsia , Humanos , Inmunoterapia , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Pronóstico , Prostatectomía , Neoplasias de la Próstata/cirugía , Neoplasias de la Próstata Resistentes a la Castración/patología , Linfocitos T Reguladores/inmunología
12.
Pediatr Hematol Oncol ; 36(4): 198-210, 2019 May.
Artículo en Inglés | MEDLINE | ID: mdl-31287345

RESUMEN

The pathogenesis of aplastic anemia (AA) in children is not clear. This study was conducted to investigate the changes in the proportion and function of regulatory T cells (Tregs) in pediatric AA. The proportion of Tregs, mRNA levels of transcription factors, and concentrations of cytokines were measured by flow cytometry, reverse transcription-PCR, and enzyme-linked immunosorbent assay, respectively. Tregs were co-cultured with effector T cells (Teff) to evaluate the function of Tregs. The proportion of Tregs after immunosuppressive therapy (IST) in pediatric AA was monitored dynamically. Compared to the control, the proportions of Tregs in peripheral blood and bone marrow lymphocytes of the untreated AA group were lower (1.31% ± 0.73% vs. 3.16% ± 0.92%, 1.49% ± 0.81% vs. 3.06% ± 0.82%, respectively, p < 0.001). The mRNA levels of FOXP3 and STAT3 in the AA group were lower (p = 0.014; p < 0.001). However, the mRNA levels of T-BET did not significantly differ between groups. The concentration of interferon-γ and interleukin-17 in the AA group were higher (p = 0.004; p = 0.003), whereas the concentration of TGF-ß decreased (p = 0.044). The immunosuppressive function of Tregs was impaired in the AA group. After IST, the proportion of Tregs was significantly lower than that in the control. The proportion of Tregs at the time of diagnosis in the nonresponsive group was lower than that in the responsive group, but the difference was not significant. Treg levels were significantly decreased and were functionally impaired at the time of diagnosis of pediatric AA. However, there was no significant change in Tregs at the resolution of AA.


Asunto(s)
Anemia Aplásica/inmunología , Células de la Médula Ósea/inmunología , Linfocitos T Reguladores/inmunología , Anemia Aplásica/patología , Células de la Médula Ósea/patología , Niño , Preescolar , Femenino , Factores de Transcripción Forkhead/inmunología , Humanos , Masculino , Proteínas de Neoplasias/inmunología , ARN Mensajero/inmunología , Factor de Transcripción STAT3/inmunología , Proteínas de Dominio T Box/inmunología , Linfocitos T Reguladores/patología
13.
Int J Mol Sci ; 20(14)2019 Jul 17.
Artículo en Inglés | MEDLINE | ID: mdl-31319604

RESUMEN

Altered adaptive immunity involving T lymphocytes has been found in depressed patients and in stress-induced depression-like behavior in animal models. Peripheral T cells play important roles in homeostasis and function of the central nervous system and thus modulate behavior. However, the T cell phenotype and function associated with susceptibility and resilience to depression remain largely unknown. Here, we characterized splenic T cells in susceptible and resilient mice after 10 days of social defeat stress (SDS). We found equally decreased T cell frequencies and comparably altered expression levels of genes associated with T helper (Th) cell function in resilient and susceptible mice. Interleukin (IL)-17 producing CD4+ and CD8+ T cell numbers in the spleen were significantly increased in susceptible mice. These animals further exhibited significantly reduced numbers of regulatory T cells (Treg) and decreased gene expression levels of TGF-ß. Mice with enhanced Th17 differentiation induced by conditional deletion of PPARγ in CD4+ cells (CD4-PPARγKO), an inhibitor of Th17 development, were equally susceptible to SDS when compared to CD4-PPARγWT controls. These data indicate that enhanced Th17 differentiation alone does not alter stress vulnerability. Thus, SDS promotes Th17 cell and suppresses Treg cell differentiation predominantly in susceptible mice with yet unknown effects in immune responses after stress exposure.


Asunto(s)
Diferenciación Celular/inmunología , Estrés Psicológico/inmunología , Linfocitos T Reguladores/inmunología , Células Th17/inmunología , Animales , Susceptibilidad a Enfermedades , Masculino , Ratones , Estrés Psicológico/patología , Linfocitos T Reguladores/patología , Células Th17/patología
14.
Cells ; 8(7)2019 07 12.
Artículo en Inglés | MEDLINE | ID: mdl-31336879

RESUMEN

Galectin-3 regulates numerous biological processes in the gut. We investigated molecular mechanisms responsible for the Galectin-3-dependent regulation of colon inflammation and evaluated whether Galectin-3 may be used as biomarker for monitoring the progression of ulcerative colitis (UC). The differences in disease progression between dextran sodium sulphate-treated wild type and Galectin-3-deficient mice were investigated and confirmed in clinical settings, in 65 patients suffering from mild, moderate, and severe colitis. During the induction phase of colitis, Galectin-3 promoted interleukin-1ß-induced polarization of colonic macrophages towards inflammatory phenotype. In the recovery phase of colitis, Galectin-3 was required for the immunosuppressive function of regulatory dendritic cells (DCs). Regulatory DCs in Galectin-3:Toll-like receptor-4:Kynurenine-dependent manner promoted the expansion of colon-infiltrated T regulatory cells (Tregs) and suppressed Th1 and Th17 cell-driven colon inflammation. Concentration of Galectin-3 in serum and stool samples of UC patients negatively correlated with clinical, endoscopic, and histological parameters of colitis. The cutoff serum values of Galectin-3 that allowed the discrimination of mild from moderate and moderate from severe colitis were 954 pg/mL and 580 pg/mL, respectively. Fecal levels of Galectin-3 higher than 553.44 pg/mL indicated attenuation of UC. In summing up, Galectin-3 regulates the cross-talk between colon-infiltrating DCs and Tregs and represents a new biomarker for monitoring the progression of UC.


Asunto(s)
Colitis Ulcerosa/patología , Células Dendríticas/patología , Galectina 3/fisiología , Linfocitos T Reguladores/patología , Adulto , Anciano , Anciano de 80 o más Años , Animales , Biomarcadores/metabolismo , Células Cultivadas , Progresión de la Enfermedad , Femenino , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad
15.
Medicina (Kaunas) ; 55(6)2019 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-31242584

RESUMEN

Background and objectives: T regulatory lymphocytes (Treg) are one of the subsets of T-lymphocytes involved in the interaction of neoplastic tumors and the host immune system, and they may impair the immune reaction against cancer. It has been shown that Treg are increased in the peripheral blood of patients with various cancers. In colorectal cancer, the prognostic role of Treg remains controversial. Colorectal cancer is a heterogenous disease, with many variations stemming from its primary tumor location. The aim of this study is to analyse the relationship between the amount of Treg in the peripheral blood of patients with left-sided colorectal cancer in various stages of disease and long-term survival. Materials and Methods: A prospective analysis of 94 patients with left-sided colorectal cancer and a group of 21 healthy volunteers was carried out. Treg levels in peripheral blood were analysed using flow cytometry. Results: There was a statistically significant difference between the amount of Treg in the Ist and IInd TNM stages (p = 0.047). The number of Treg in the entire study group was significantly lower than in the control group (p = 0.008) and between patients in stages II and III and the control group (p = 0.003 and p = 0.018). The group of pT3+pT4 patients also had significantly lower Treg counts in their peripheral blood than the control group (p = 0.005). In the entire study group, the level of Treg cells in the peripheral blood had no influence on survival. The analysis of the TNM stage subgroups also showed no difference in survival between patients with "low" and "high" Treg counts. Conclusion: The absolute number of Treg in the peripheral blood of patients with left-sided colorectal cancer was significantly decreased in comparison to healthy controls, especially for patients with stage II+III disease. Treg presence in the peripheral blood had no impact on survival.


Asunto(s)
Biomarcadores/análisis , Neoplasias Colorrectales/sangre , Linfocitos T Reguladores/fisiología , Adulto , Biomarcadores/sangre , Neoplasias Colorrectales/fisiopatología , Femenino , Citometría de Flujo/métodos , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Estudios Prospectivos , Linfocitos T Reguladores/patología
16.
Immunology ; 157(3): 187-189, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-31225653

RESUMEN

There have been substantial strides forward in our understanding of the contribution of regulatory T (Treg) cells to cancer immunosuppression. In this issue, we present a series of papers highlighting emerging themes on this topic relevant not only to our understanding of the fundamental biology of tumour immunosuppression but also to the design of new immunotherapeutic approaches. The substantially shared biology of CD4+ conventional T (Tconv) and Treg cells necessitates a detailed understanding of the potentially opposing functional consequences that immunotherapies will have on Treg and Tconv cells, a prominent example being the potential for Treg-mediated hyperprogressive disease following anti-PD-1 therapy. Such understanding will aid patient stratification and the rational design of combination therapies. It is also becoming clear, however, that Treg cells within tumours exhibit distinct biological features to both Tconv cells and Treg cells in other tissues. These distinct features provide the opportunity for development of targeted immunotherapies with greater efficacy and reduced potential for inducing systemic toxicity.


Asunto(s)
Linfocitos Infiltrantes de Tumor/inmunología , Neoplasias/inmunología , Linfocitos T Reguladores/inmunología , Escape del Tumor , Animales , Humanos , Inmunoterapia/efectos adversos , Linfocitos Infiltrantes de Tumor/patología , Neoplasias/patología , Neoplasias/terapia , Fenotipo , Transducción de Señal , Linfocitos T Reguladores/patología
17.
J Biosci ; 44(2)2019 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-31180054

RESUMEN

This study was conducted to determine whether exposure to particulate matter 2.5 (PM2.5) affects the immune tolerance of neonatal mice via the regulation of PD-L1 expression. One-week-old BALB/c mice were exposed to PM2.5 for 8 days. From day 8 to day 18, the mice were treated with 5 µg house dust mite (HDM) (i. n.) every two days. Adenovirus-carried PD-L1 overexpression vectors were infected into mice via nasal inhalation 6 days after exposure to PM2.5. Airway hyperresponsiveness (AHR) was examined in mice 19 days after exposure to PM2.5, and the related parameters of airway inflammation were studied on day 22. Co-exposure to PM2.5 and HDM reduced PD-L1 expression but greatly increased infiltration of inflammatory cells, which was reversed by PD-L1 overexpression. Co-exposure to PM2.5 and HDM also elevated serum IL-4, IL-5 and IL-13 levels and reduced TGF-ß level. Exposure to PM2.5 alone slightly increased the numbers of dendritic cells (DCs) but reduced the numbers of antigen-presenting cells expressing PD-L1 and Treg cells. Therefore, early exposure to PM2.5 reduced PD-L1 expression in the lungs of neonatal mice, which interfered with immune tolerance establishment and subsequently resulted in allergic airway inflammation.


Asunto(s)
Antígeno B7-H1/inmunología , Células Dendríticas/efectos de los fármacos , Tolerancia Inmunológica/efectos de los fármacos , Pulmón/efectos de los fármacos , Material Particulado/administración & dosificación , Hipersensibilidad Respiratoria/inmunología , Adenoviridae/genética , Adenoviridae/inmunología , Administración por Inhalación , Animales , Animales Recién Nacidos , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/genética , Células Dendríticas/inmunología , Células Dendríticas/patología , Regulación de la Expresión Génica , Vectores Genéticos/administración & dosificación , Vectores Genéticos/química , Vectores Genéticos/inmunología , Interleucina-13/genética , Interleucina-13/inmunología , Interleucina-4/genética , Interleucina-4/inmunología , Interleucina-5/genética , Interleucina-5/inmunología , Pulmón/inmunología , Pulmón/patología , Ratones , Ratones Endogámicos BALB C , Pyroglyphidae/química , Pyroglyphidae/inmunología , Hipersensibilidad Respiratoria/inducido químicamente , Hipersensibilidad Respiratoria/genética , Hipersensibilidad Respiratoria/patología , Transducción de Señal , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/patología , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/inmunología
18.
PLoS Pathog ; 15(6): e1007866, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-31188899

RESUMEN

The gastric lamina propria of mice that have been experimentally infected with the pathobiont Helicobacter pylori hosts a dense network of myeloid cells that includes BATF3-dependent CD103+ dendritic cells (DCs). We show here that CD103+ DCs are strictly required for gastric Th1 responses to H. pylori and for H. pylori infection control. A similar dependence of type 1 immunity on CD103+ DCs is observed in a Mycobacterium bovis BCG infection model, and in a syngeneic colon cancer model. Strikingly, we find that not only the expansion and/or recruitment of Th1 cells, but also of peripherally induced, neuropilin-negative regulatory T-cells to sites of infection requires BATF3-dependent DCs. A shared feature of the examined models is the strongly reduced production of the chemokines and CXCR3 ligands CXCL9, 10 and 11 in BATF3-deficient mice. The results implicate BATF3-dependent DCs in the recruitment of CXCR3+ effector and regulatory T-cells to target tissues and in their local expansion.


Asunto(s)
Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/inmunología , Células Dendríticas/inmunología , Infecciones por Helicobacter/inmunología , Helicobacter pylori/inmunología , Mycobacterium bovis/inmunología , Proteínas Represoras/inmunología , Linfocitos T Reguladores/inmunología , Tuberculosis/inmunología , Animales , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Línea Celular Tumoral , Quimiocinas CXC/genética , Quimiocinas CXC/inmunología , Células Dendríticas/microbiología , Células Dendríticas/patología , Infecciones por Helicobacter/genética , Infecciones por Helicobacter/patología , Ratones , Ratones Noqueados , Receptores CXCR3/genética , Receptores CXCR3/inmunología , Proteínas Represoras/genética , Linfocitos T Reguladores/microbiología , Linfocitos T Reguladores/patología , Tuberculosis/genética , Tuberculosis/patología
19.
Inflammation ; 42(5): 1705-1718, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31209730

RESUMEN

Treg cells are crucial for maintaining immune homeostasis in CP/CPPS, but the molecular mechanisms underlying the modulation of the function of Treg in CP/CPPS remain unclear. The main purpose of this study is to investigate the relationship between immunosuppressive function of Treg and the methylation level of Foxp3 promoter in experimental autoimmune prostatitis (EAP) mouse model. EAP model was induced by subcutaneous injecting prostate-steroid-binding protein (PSBP) and complete Freund's adjuvant with NOD mice. Histological analysis revealed that EAP model was successfully induced. The expression of IFN-γ was increased, and TGF-ß was decreased in the serum of EAP, respectively. The percentage of Tregs in splenic lymphocyte was increased in EAP. The suppressive ability of Tregs on Teffs was impaired in EAP. The methylation level of Foxp3 promoter was increased, and the expression of Foxp3 was decreased in EAP. By injection AZA which was DNA-methylation inhibitor into EAP mice, prostate inflammation was alleviated, expressions of TGF-ß and Foxp3 were increased, and the suppressive function of Tregs was improved in vitro and in vivo. Thus, we concluded that aberrant increased methylation of Foxp3 promoter in Treg cells leads to the impaired suppressive function of Treg cells, exacerbating autoimmune inflammatory injury in EAP.


Asunto(s)
Metilación de ADN , Factores de Transcripción Forkhead/genética , Prostatitis/inmunología , Linfocitos T Reguladores/inmunología , Animales , Autoinmunidad , Modelos Animales de Enfermedad , Factores de Transcripción Forkhead/metabolismo , Inflamación/inmunología , Masculino , Ratones , Regiones Promotoras Genéticas , Prostatitis/patología , Linfocitos T Reguladores/patología
20.
PLoS One ; 14(5): e0216893, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31120919

RESUMEN

CD4+ effector/memory T cells (Tem) represent a leading edge of the adaptive immune system responsible for protecting the body from infection, cancer, and other damaging processes. However, a subset of Tem cells with low expression of CD45Rb (RbLoTem) has been shown to suppress inflammation despite their effector surface phenotype and the lack of FoxP3 expression, the canonical transcription factor found in most regulatory T cells. In this report, we show that RbLoTem cells can suppress inflammation by influencing Treg behavior. Co-culturing activated RbLoTem and Tregs induced high expression of IL-10 in vitro, and conditioned media from RbLoTem cells induced IL-10 expression in FoxP3+ Tregs in vitro and in vivo, indicating that RbLoTem cells communicate with Tregs in a cell-contact independent fashion. Transcriptomic and multi-analyte Luminex data identified both IL-2 and IL-4 as potential mediators of RbLoTem-Treg communication, and antibody-mediated neutralization of either IL-4 or CD124 (IL-4Rα) prevented IL-10 induction in Tregs. Moreover, isolated Tregs cultured with recombinant IL-2 and IL-4 strongly induced IL-10 production. Using house dust mite (HDM)-induced airway inflammation as a model, we confirmed that the in vivo suppressive activity of RbLoTem cells was lost in IL-4-ablated RbLoTem cells. These data support a model in which RbLoTem cells communicate with Tregs using a combination of IL-2 and IL-4 to induce robust expression of IL-10 and suppression of inflammation.


Asunto(s)
Asma/inmunología , Comunicación Celular/inmunología , Interleucina-10/inmunología , Interleucina-4/inmunología , Antígenos Comunes de Leucocito/inmunología , Modelos Inmunológicos , Linfocitos T Reguladores/inmunología , Animales , Asma/genética , Asma/patología , Comunicación Celular/genética , Modelos Animales de Enfermedad , Inflamación/genética , Inflamación/inmunología , Inflamación/patología , Interleucina-10/genética , Interleucina-2/genética , Interleucina-2/inmunología , Interleucina-4/genética , Antígenos Comunes de Leucocito/genética , Ratones , Ratones Noqueados , Pyroglyphidae/inmunología , Linfocitos T Reguladores/patología
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