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1.
Immunopharmacol Immunotoxicol ; 41(3): 386-393, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30422018

RESUMO

Objective: Recently, immune checkpoints blockers showed higher anti-tumor activity for advanced gastric cancer (GC). The purpose of the study is to find out predictive biomarkers related to anti-cytotoxic lymphocyte antigen 4 (CTLA4) therapy. Materials and methods: Datasets of gene expression omnibus (GEO), the cancer genome atlas (TCGA), and gene set enrichment analysis (GESA) were extracted. Differential expression of CTLA4 between cancer tissues and normal mucosa, enrichment of WT (wild type) vs. CTLA4_KO (knockout) upregulated gene set and clinical significance were analyzed. The expression of CTLA4, CD3, and granzyme A (GZMA) were validated on 30 cases of Chinese GC. Microsatellite instability (MSI) marker MLH1 and Epstein-Barr virus (EBV) marker EBER were examined on 30 cases of Chinese GC by immunohistochemistry and in situ hybridization. Results: CTLA4 was upregulated in GC tissue relative to normal mucosa in datasets of GSE27342 (fold change = 1.586, p < .001) and GSE63089 (fold change = 1.365, p < .001). Increased CTLA4 expression was positively related to CTLA4 activation. EBV-associated GC (EBVaGC) and microsatellite instability GC (MSIGC) disclosed higher CTLA4 levels than other GCs. Genomic stability GC (GSGC) also showed higher enrichment score of CTLA4 activation. CTLA4 activation resulted in shorter overall survival in GC. The expression level of CTLA4 was well correlated to expression levels of GZMA (R = 0.701, p < .001) and CD3 (R = 0.750, p < .001). Conclusions: Based on bioinformatics analysis, GSGC should be worth noticed as a potential GC subtypes responsive to anti-CTLA4 treatment.


Assuntos
Antígeno CTLA-4 , Bases de Dados de Ácidos Nucleicos , Regulação Neoplásica da Expressão Gênica/imunologia , Neoplasias Gástricas , Grupo com Ancestrais do Continente Asiático , Antígeno CTLA-4/biossíntese , Antígeno CTLA-4/genética , Antígeno CTLA-4/imunologia , China , Feminino , Humanos , Masculino , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/imunologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia
2.
Nat Commun ; 9(1): 5344, 2018 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-30559442

RESUMO

Foxp3-expressing CD4+ regulatory T (Treg) cells need to differentiate into effector Treg (eTreg) cells to maintain immune homeostasis. T-cell receptor (TCR)-dependent induction of the transcription factor IRF4 is essential for eTreg differentiation, but how IRF4 activity is regulated in Treg cells is still unclear. Here we show that the AP-1 transcription factor, JunB, is expressed in eTreg cells and promotes an IRF4-dependent transcription program. Mice lacking JunB in Treg cells develop multi-organ autoimmunity, concomitant with aberrant activation of T helper cells. JunB promotes expression of Treg effector molecules, such as ICOS and CTLA4, in BATF-dependent and BATF-independent manners, and is also required for homeostasis and suppressive functions of eTreg. Mechanistically, JunB facilitates the accumulation of IRF4 at a subset of IRF4 target sites, including those located near Icos and Ctla4. Thus, JunB is a critical regulator of IRF4-dependent Treg effector programs, highlighting important functions for AP-1 in Treg-mediated immune homeostasis.


Assuntos
Fatores Reguladores de Interferon/metabolismo , Ativação Linfocitária/imunologia , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia , Fatores de Transcrição/metabolismo , Animais , Autoimunidade/genética , Autoimunidade/imunologia , Antígeno CTLA-4/biossíntese , Diferenciação Celular/imunologia , Proteína Coestimuladora de Linfócitos T Induzíveis/biossíntese , Ativação Linfocitária/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Linfócitos T Auxiliares-Indutores/imunologia , Fatores de Transcrição/genética
3.
J Neuroimmunol ; 323: 105-108, 2018 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-30196822

RESUMO

Multiple sclerosis (MS), is an autoimmune disorder of central nervous system (CNS) characterized by inflammation and demyelination. Self-tolerance impairment is considered to be induced by a combination of inherited susceptibility and environmental agents. In this work, we demonstrate that a reduction in the comparative expression of well-known inhibitory receptors (i.e., CTLA-4, PD-1, and TIM-3) is importantly linked with MS patients compared to healthy controls. The relative expression of interested genes was performed on peripheral blood mononuclear cells (PBMCs), by using quantitative real time-PCR (qRT-PCR). Our data highlighted the role of inhibitory receptors in the maintenance of immune homeostasis in autoimmune disease.


Assuntos
Antígeno CTLA-4/sangue , Regulação para Baixo/fisiologia , Receptor Celular 2 do Vírus da Hepatite A/sangue , Esclerose Múltipla/sangue , Receptor de Morte Celular Programada 1/sangue , Adulto , Antígeno CTLA-4/biossíntese , Antígeno CTLA-4/genética , Feminino , Expressão Gênica , Receptor Celular 2 do Vírus da Hepatite A/biossíntese , Receptor Celular 2 do Vírus da Hepatite A/genética , Humanos , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/genética , Esclerose Múltipla/metabolismo , Receptor de Morte Celular Programada 1/biossíntese , Receptor de Morte Celular Programada 1/genética
4.
J Immunol Res ; 2018: 3096183, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30013989

RESUMO

Background: Treg cells play an important role in the pathogenic progress of asthma. Objective: To address the alterations of Treg cells in asthma. Methods: Proliferation-and function-associated markers of Treg cells along with the percentage of Treg cells producing some cytokine from asthmatics and healthy subjects were analyzed by flow cytometry. Besides, the expressions of USP21 and PIM2 in Treg cells were measured by cell immunochemistry after Treg cells were sorted. Results: Treg cells from asthmatic patients showed lower proliferation activity and were more likely to be apoptotic. These cells expressed lower levels of GITR, CTLA-4, Nrp-1, and IL-10 compared to those from the healthy control. Th2-like Treg cells increased in asthmatic patients, while the percentage of IFN-r+ Treg cells was similar between two groups. Moreover, the percentage of IL-4+ Treg cells is related to the asthma control. Treg cells from asthmatic patients expressed more FOXP3 as well as GATA3; the expression level of GATA3 negatively correlated with FEV1%pred. Increased expressions of USP21 and PIM2 in Treg cells from asthmatic patients were found. Conclusion: Treg cells decreased in asthmatic patients, with an impaired immunosupression function and a Th2-like phenotype, which may be due to overexpression of GATA3 and FOXP3, regulated by USP21 and PIM2, respectively.


Assuntos
Asma/imunologia , Fatores de Transcrição Forkhead/sangue , Fator de Transcrição GATA3/sangue , Linfócitos T Reguladores/imunologia , Adolescente , Adulto , Idoso , Asma/sangue , Biomarcadores/sangue , Antígeno CTLA-4/biossíntese , Antígeno CTLA-4/sangue , Antígeno CTLA-4/imunologia , Estudos de Casos e Controles , Fatores de Transcrição Forkhead/imunologia , Fator de Transcrição GATA3/imunologia , Humanos , Tolerância Imunológica , Interleucina-10/sangue , Interleucina-10/imunologia , Pessoa de Meia-Idade , Células Th2/imunologia , Ubiquitina Tiolesterase/biossíntese , Ubiquitina Tiolesterase/sangue , Ubiquitina Tiolesterase/imunologia , Adulto Jovem
5.
Front Immunol ; 9: 19, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29403500

RESUMO

Human immunodeficiency virus type-1 (HIV-1) elite controllers (ELCs) represent a unique population that control viral replication in the absence of antiretroviral therapy (cART). It is well established that expression of multiple inhibitory receptors on CD8+ T cells is associated with HIV-1 disease progression. However, whether reduced co-expression of inhibitory receptors on CD4+ T cells is linked to natural viral control and slow HIV-1 disease progression remains undefined. Here, we report on the expression pattern of numerous measurable inhibitory receptors, associated with T cell exhaustion (programmed cell death-1, CTLA-4, and TIGIT), on different CD4+ T cell memory populations in ELCs and HIV-infected subjects with or without long-term cART. We found that the co-expression pattern of inhibitory receptors was significantly reduced in ELCs compared with HIV-1 cART-treated and viremic subjects, and similar to healthy controls. Markers associated with T cell exhaustion varied among different memory CD4+ T cell subsets and highest levels were found mainly on transitional memory T cells. CD4+ T cells co-expressing all inhibitory markers were positively correlated to T cell activation (CD38+ HLA-DR+) as well as the transcription factors Helios and FoxP3. Finally, clinical parameters such as CD4 count, HIV-1 viral load, and the CD4/CD8 ratio all showed significant associations with CD4+ T cell exhaustion. We demonstrate that ELCs are able to maintain lower levels of CD4+ T cell exhaustion despite years of ongoing viral replication compared with successfully cART-treated subjects. Our findings suggest that ELCs harbor a "healthy" state of inhibitory receptor expression on CD4+ T cells that might play part in maintenance of their control status.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , HIV-1/imunologia , Memória Imunológica/imunologia , Ativação Linfocitária/imunologia , ADP-Ribosil Ciclase 1/biossíntese , Contagem de Linfócito CD4 , Relação CD4-CD8 , Antígeno CTLA-4/biossíntese , Fatores de Transcrição Forkhead/biossíntese , Antígenos HLA-DR/biossíntese , Humanos , Fator de Transcrição Ikaros/biossíntese , Glicoproteínas de Membrana/biossíntese , Receptor de Morte Celular Programada 1/biossíntese , Receptores Imunológicos/biossíntese , Carga Viral , Replicação Viral
6.
Asia Pac J Clin Oncol ; 14(5): e252-e258, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29368793

RESUMO

AIM: To better understand the T-cell immunodeficiency status in patients with peripheral T-cell lymphomas (PTCLs) and NK/T-cell lymphomas (NK/T-CLs), the T-cell inhibitory receptors expression pattern was investigated. METHODS: The expression levels of programmed death 1 (PD-1), cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), B/T lymphocyte attenuator (BTLA), lymphocyte-activation gene 3 (LAG-3), T-cell immunoglobulin-3 (TIM-3), T-cell immunoglobulin and ITIM domain (TIGIT) genes were detected in peripheral blood mononuclear cells (PBMCs) from patients and healthy volunteers by quantitative real-time-PCR, the correlation between different gene expression levels was analyzed. RESULTS: Significantly higher expression of PD-1, CTLA-4, BTLA, LAG-3, TIM-3 and TIGIT can be observed as a common characteristic in patients with PTCL or NK/T-CL. However, the coexpression pattern seemed different between subtypes. Their overexpression is also related to disease progression stage. CONCLUSION: We first characterized the expression pattern of six T-cell inhibitory receptor genes in PTCL and NK/T-CL, which might work as immune biomarkers for evaluation the immunosuppression status and help to establish the precision targets of immunotherapy.


Assuntos
Biomarcadores Tumorais/imunologia , Linfoma Extranodal de Células T-NK/imunologia , Linfoma de Células T Periférico/imunologia , Antígenos CD/análise , Antígenos CD/biossíntese , Antígeno CTLA-4/análise , Antígeno CTLA-4/biossíntese , Feminino , Receptor Celular 2 do Vírus da Hepatite A/análise , Receptor Celular 2 do Vírus da Hepatite A/biossíntese , Humanos , Receptor de Morte Celular Programada 1/análise , Receptor de Morte Celular Programada 1/biossíntese , Receptores Imunológicos/análise , Receptores Imunológicos/biossíntese
7.
J Immunol ; 200(3): 909-914, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29282307

RESUMO

Regulatory T cells (Tregs) use a distinct TCR repertoire and are more self-reactive compared with conventional T cells. However, the extent to which TCR affinity regulates the function of self-reactive Tregs is largely unknown. In this study, we used a two-TCR model to assess the role of TCR affinity in Treg function during autoimmunity. We observed that high- and low-affinity Tregs were recruited to the pancreas and contributed to protection from autoimmune diabetes. Interestingly, high-affinity cells preferentially upregulated the TCR-dependent Treg functional mediators IL-10, TIGIT, GITR, and CTLA4, whereas low-affinity cells displayed increased transcripts for Areg and Ebi3, suggesting distinct functional profiles. The results of this study suggest mechanistically distinct and potentially nonredundant roles for high- and low-affinity Tregs in controlling autoimmunity.


Assuntos
Autoimunidade/imunologia , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/prevenção & controle , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Anfirregulina/biossíntese , Animais , Antígeno CTLA-4/biossíntese , Adesão Celular/imunologia , Proteína Relacionada a TNFR Induzida por Glucocorticoide/biossíntese , Interleucina-10/biossíntese , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Antígenos de Histocompatibilidade Menor/biossíntese , Pâncreas/citologia , Pâncreas/imunologia , Receptores de Citocinas/biossíntese , Receptores Imunológicos/biossíntese
8.
Eur J Immunol ; 48(1): 151-160, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28845512

RESUMO

VZV-reactivation may lead to symptomatic central nervous system (CNS) diseases, but identification of VZV as causative pathogen of CNS-diseases is challenging. This study was performed to characterize VZV-specific T cells from cerebrospinal fluid (CSF) and blood of patients with active CNS-disease and to determine whether this may improve differential diagnosis. 27 patients with pleocytosis in the CSF were recruited and classified into three groups (10 VZV-related, 10 non-VZV-related, 7 unclear). VZV-specific CD4+ T cells were quantified in CSF and blood after simultaneous stimulation with a VZV-antigen lysate and detection of cytokines (IFN-γ, IL-2, TNF-α) and CTLA-4. Polyclonal stimulation served as positive control. VZV-specific CD4+ T-cell frequencies were highest in both CSF (p = 0.0001) and blood (p = 0.011) of patients with VZV-infection, and were enriched at the site of infection (p = 0.002). While cytokine-expression profiles only showed minor differences between the groups, CTLA-4-expression levels on VZV-specific T cells from CSF and blood were significantly increased in VZV-related CNS-infections (p = 0.0002 and p<0.0001) and clearly identified VZV-related CNS-diseases (100% sensitivity and 100% specificity). Polyclonally stimulated T cells did not show any quantitative and phenotypical differences between the groups. Increased frequency and CTLA-4-expression of VZV-specific T cells from CSF or blood are specifically found in patients with VZV-related CNS-infection.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Antígeno CTLA-4/biossíntese , Infecções do Sistema Nervoso Central/virologia , Herpesvirus Humano 3/imunologia , Imunidade Celular/imunologia , Adulto , Sangue/virologia , Infecções do Sistema Nervoso Central/imunologia , Líquido Cefalorraquidiano/virologia , Feminino , Herpesvirus Humano 3/metabolismo , Humanos , Interferon gama/sangue , Interleucina-2/sangue , Masculino , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/sangue , Ativação Viral/imunologia
9.
Cancer Immunol Immunother ; 66(11): 1449-1461, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28707078

RESUMO

The immune checkpoint receptor CTLA-4 plays a crucial part in negatively regulating T cell activation and maintaining self-tolerance. It is frequently overexpressed in a variety of malignancies, yet its prognostic impact in non-small cell lung cancer (NSCLC) remains unclear. We constructed tissue microarrays from tumor tissue samples and evaluated the immunohistochemical expression of CTLA-4 in 536 patients with primary resected stage I-IIIA NSCLC. Expression of CTLA-4 was analyzed in tumor and stromal primary tumor tissue and in locoregional metastatic lymph nodes. CTLA-4 expression in neither tumor epithelial cells (T-CTLA-4) nor stromal cells (S-CTLA-4) of primary tumors was significantly associated with disease-specific survival (DSS) in all patients. However, high S-CTLA-4 expression independently predicted significantly improved DSS in the squamous cell carcinoma subgroup (HR 0.62, 95% CI 0.41-0.93, P = 0.021). In contrast, there was an independent negative prognostic impact of T-CTLA-4 expression in metastatic lymph nodes (HR 1.65, 95% CI 1.03-2.65, P = 0.039). Our results indicate that the expression of CTLA-4 has diverging prognostic impacts in metastatic NSCLC lymph nodes versus primary tumors. The presented results highlight important differences in the tumor microenvironments of primary and metastatic NSCLC tissues, and have potential to guide treatment and clinical sampling strategies.


Assuntos
Antígeno CTLA-4/biossíntese , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , Microambiente Tumoral , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica/estatística & dados numéricos , Neoplasias Pulmonares/patologia , Linfonodos/patologia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos
10.
Acta Trop ; 172: 58-63, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28454880

RESUMO

The pathological events in human cerebral malaria are mimicked in the experimental cerebral malaria (ECM) in Plasmodium berghei ANKA (PBA)-infected C57BL/6 mice. Although previously implied in ECM, the kinetics of cytokines and chemokines expression-an essential functional feature for defining causality in ECM development-remained untested. Herein, we characterized the immunopathological changes and the expression of negative immune regulatory molecules, cytokines and chemokines through asymptomatic (3days after infection, 3dpi), symptomatic (5dpi) and ECM (7dpi) stages in PBA-infected C57BL/6 mice. Parasitized RBCs were first detected in brain on 3dpi, edema and tissue alterations on 5dpi, and hemorrhages in different areas of brain on 7dpi. Increased cerebellar PD-1, CTLA-4 and LAG-3 expression and reduced hippocampal CXCL-4 expression on 3dpi were the first observed immunological changes. The negative immune regulatory molecules (PD-L1, CTLA-4), cytokines (TNF-α, sFAS-L), and chemokines (CXCL-10, MIP-1ß) transcript levels varied in different brain areas in symptomatic and ECM phases. By 5dpi, TNF-α, CXCL10 and MIP-1ß significantly increased in all brain parts studied; IL-1RA in whole brain, whereas CXCL4 reduced in hippocampus and cerebrum. By 7dpi, the hippocampal PD-1, CXCL4 and CTLA-4 expression decreased but the cerebral, cerebellar and hippocampal PD-L1 expression were elevated. TNF-α, CXCL10, MIP-1ß, PD-1, CTLA-4 and PD-L1 expression were up-regulated in different brain areas. The TNFR2, IFN-gamma receptor, Lymphotoxin-ß receptor and sFAS-L transcripts significantly increased in brain in ECM. Our data characterize key dynamic immunopathological changes in brain to imply relationship to ECM development.


Assuntos
Malária Cerebral/imunologia , Animais , Antígeno CTLA-4/biossíntese , Quimiocinas/imunologia , Citocinas/biossíntese , Feminino , Humanos , Fatores Imunológicos , Proteína Antagonista do Receptor de Interleucina 1/biossíntese , Camundongos , Camundongos Endogâmicos C57BL , Plasmodium berghei/imunologia , Fator de Necrose Tumoral alfa/biossíntese
11.
Cancer Immunol Immunother ; 66(5): 627-636, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28236118

RESUMO

V-domain Ig suppressor of T cell activation (VISTA), a novel immune checkpoint regulatory molecule, suppresses T cell mediated immune responses. The aim of the present study was to profile the immunological expression, clinical significance and correlation of VISTA in human oral squamous cell carcinoma (OSCC). Human tissue microarrays, containing 165 primary OSCCs, 48 oral epithelial dysplasias and 43 normal oral mucosae, were applied to investigate the expression levels of VISTA, CD8, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), programmed death ligand 1 (PD-L1), PI3Kα p110, IL13Rα2, phospho-STAT3 at tyrosine 705 (p-STAT3) and myeloid-derived suppressor cell (MDSC) markers (CD11b and CD33) by immunohistochemistry and digital pathology analysis. The results demonstrated that the protein level of VISTA was significantly higher in human OSCC specimens, and that VISTA expression in primary OSCCs was correlated with lymph node status. VISTA expression did not serve as an independent predictor for poor prognosis, while patient subgroup with VISTA high and CD8 low expression (22/165) had significantly poorer overall survival compared with other subgroups based on the multivariate and Cox hazard analyses among the primary OSCC patients in the present cohort. Additionally, the expression of VISTA was significantly correlated with PD-L1, CTLA-4, IL13Rα2, PI3K, p-STAT3, CD11b and CD33 according to Pearson's correlation coefficient test. Taken together, the results indicated that the VISTA high and CD8 low group, as an immunosuppressive subgroup, might be associated with a poor prognosis in primary OSCC. These findings indicated that VISTA might be a potential immunotherapeutic target in OSCC treatment.


Assuntos
Antígenos B7/biossíntese , Antígenos CD8/imunologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/imunologia , Neoplasias Bucais/imunologia , Antígeno B7-H1/biossíntese , Antígeno CTLA-4/biossíntese , Carcinoma de Células Escamosas/patologia , Humanos , Imunossupressão , Neoplasias Bucais/genética , Neoplasias Bucais/patologia , Prognóstico , Fator de Transcrição STAT3/biossíntese , Análise de Sobrevida
12.
Oncotarget ; 8(8): 13703-13715, 2017 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-28099147

RESUMO

Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), a potent immunoregulatory molecule, can down-regulate T-cell activation and inhibit anti-tumor immune response. This study showed that LPS-stimulated human dendritic cells (DCs) decreased the expression of HLA-DR, CD83 and costimulatory molecules (CD40, CD80 and CD86) following coculturing with CTLA-4+ breast cancer cells. Moreover, the suppressed DCs further inhibited proliferation of allogeneic CD4+/CD8+ T-cells, differentiation of Th1 and function of cytotoxic lymphocytes (CTLs). However, CTLA-4 blockade in breast cancer cells could recover DC maturation and cytokine production, elevate antigen-presenting function of DCs, reverse Th1/CTLs response and cytokine secretion. Subsequent study demonstrated that the activation of extracellular-signal regulated kinase and signal transducer and activator of transcription 3 of DCs caused by CTLA-4+ breast cancer cells were the predominant mechanism of DC suppression. In addition, CTLA-4 blockade treatment also directly inhibited proliferation and induced apoptosis of CTLA-4+ breast cancer cells. Collectively, CTLA-4 was expressed and functional on human breast cancer cells through influencing maturation and function of DCs in vitro, and CTLA-4 blockage not only recovered the antigen-presenting function of DCs and T-cells activation but also suppressed the biological activity of breast cancer cells themselves. This study highlights the clinical application of CTLA-4 blockade therapy in breast cancer.


Assuntos
Neoplasias da Mama/imunologia , Antígeno CTLA-4/imunologia , Células Dendríticas/imunologia , Apresentação do Antígeno , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/biossíntese , Citocinas/biossíntese , Citocinas/imunologia , Células Dendríticas/patologia , Feminino , Citometria de Fluxo , Humanos , Células MCF-7 , Monócitos/imunologia , Monócitos/patologia , Células Th1/imunologia , Células Th1/patologia
13.
Nat Rev Endocrinol ; 13(4): 195-207, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28106152

RESUMO

Advances in cancer therapy in the past few years include the development of medications that modulate immune checkpoint proteins. Cytotoxic T-lymphocyte antigen 4 (CTLA4) and programmed cell death protein 1 (PD1) are two co-inhibitory receptors that are expressed on activated T cells against which therapeutic blocking antibodies have reached routine clinical use. Immune checkpoint blockade can induce inflammatory adverse effects, termed immune-related adverse events (IRAEs), which resemble autoimmune disease. In this Review, we describe the current data regarding immune-related endocrinopathies, including hypophysitis, thyroid dysfunction and diabetes mellitus. We discuss the clinical management of these endocrinopathies within the context of our current understanding of the mechanisms of IRAEs.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Doenças do Sistema Endócrino/induzido quimicamente , Doenças do Sistema Endócrino/imunologia , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Animais , Anticorpos Monoclonais/efeitos adversos , Antígeno CTLA-4/biossíntese , Doenças do Sistema Endócrino/metabolismo , Humanos , Imunoterapia/efeitos adversos , Ipilimumab , Neoplasias/metabolismo , Receptor de Morte Celular Programada 1/biossíntese
14.
Mol Immunol ; 82: 57-65, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28027499

RESUMO

Accumulating evidence suggests an association between immune dysfunction and autism disorders in a significant subset of children. In addition, an imbalance between pro- and anti-inflammatory pathways has been proposed to play an important role in the pathogenesis of several neurodevelopmental disorders including autism; however, the role of anti-inflammatory molecules IL-27 and CTLA-4 and pro-inflammatory cytokines IL-21 and IL-22 has not previously been explored in autistic children. In the current study, we investigated the expression of IL-21, IL-22, IL-27, and CD152 (CTLA-4) following an in-vitro immunological challenge of peripheral blood mononuclear cells (PBMCs) from children with autism (AU) or typically-developing children (TD) with phorbol-12-myristate 13-acetate (PMA) and ionomycin. In our study, cells from children with AU had increased IL-21 and IL-22 and decreased CTLA-4 expression on CD4+ T cells as compared with cells from the TD control. Similarly, AU cells showed decreased IL-27 production by CD14+ cells compared to that of TD control cells. These results were confirmed by real-time PCR and western blot analyses. Our study shows dysregulation of the immune balance in cells from autistic children as depicted by enhanced pro-inflammatory cytokines, 'IL-21/IL-22' and decreased anti-inflammatory molecules, 'IL-27/CTLA-4'. Thus, further study of this immune imbalance in autistic children is warranted in order to facilitate development of biomarkers and therapeutics.


Assuntos
Transtorno Autístico/imunologia , Biomarcadores/análise , Citocinas/biossíntese , Citocinas/imunologia , Leucócitos Mononucleares/imunologia , Western Blotting , Antígeno CTLA-4/biossíntese , Antígeno CTLA-4/imunologia , Criança , Pré-Escolar , Estudos Transversais , Feminino , Citometria de Fluxo , Humanos , Inflamação/imunologia , Interleucinas/biossíntese , Interleucinas/imunologia , Masculino , Reação em Cadeia da Polimerase em Tempo Real
15.
Cancer Immunol Immunother ; 66(2): 161-170, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27866241

RESUMO

Regulatory T cells (Tregs) play an important role in the suppression of the immune response in lung cancer. Cytotoxic T-lymphocyte antigen 4 (CTLA-4) expressed on T lymphocytes is capable of downregulating cytotoxic T cells and is constitutively expressed on Tregs. Little is known about the population of Tregs with two forms of CTLA-4: surface (s) and intracellular (in) in the lung cancer environment. Th17 cells defined by production of IL-17 have pleiotropic functions in anticancer immune response. Our aim was to detect the elements of immune response regulation in lung cancer in three compartments: by analysis of bronchoalveolar lavage fluid (BALF) from the lung affected by cancer (clBALF), healthy symmetrical lung (hlBALF) and peripheral blood (PB) from the same patient. A total of 54 samples were collected. Tregs, (s)CTLA-4, (in)CTLA-4 were detected by flow cytometry with antibodies against CD4, CD25, Foxp3, CD127, CTLA-4, and concentration of IL-17 was estimated by ELISA. We observed a significantly higher proportion of Tregs in clBALF than in hlBALF or PB (8.5 vs. 5.0 vs. 5.1%, respectively, p < 0.05). The median proportion of (in)CTLA-4+ Tregs was higher in clBALF than in hlBALF or PB (89.0, 81.5, 56.0%, p < 0.05). IL-17 concentration was the highest in clBALF-6.6 pg/ml. We observed a significant correlation between the proportion of Tregs and (in)CTLA-4+ Tregs with IL-17A concentration in clBALF. We confirmed significant differences in the proportion of regulatory elements between cancerous lung and healthy lung and PB and the usefulness of BALF analysis in evaluation of immune response regulation in local lung cancer environment.


Assuntos
Antígeno CTLA-4/biossíntese , Interleucina-17/biossíntese , Neoplasias Pulmonares/imunologia , Linfócitos T Reguladores/imunologia , Microambiente Tumoral/imunologia , Idoso , Idoso de 80 Anos ou mais , Antígeno CTLA-4/imunologia , Feminino , Humanos , Interleucina-17/imunologia , Masculino , Pessoa de Meia-Idade
16.
PLoS Genet ; 12(12): e1006477, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28027300

RESUMO

Prostate cancer incidence is increasing in younger men. We investigated whether men diagnosed with Gleason 7 (3+4) T2 prostate cancer at younger ages (≤ 45 years, young cohort) had different mRNA and miRNA expression profiles than men diagnosed at older ages (71-74 years, older cohort). We identified differentially expressed genes (DEGs) related to tumor-normal differences between the cohorts. Subsequent pathway analysis of DEGs revealed that the young cohort had significantly more pronounced inflammatory and immune responses to tumor development compared to the older cohort. Further supporting a role of inflammation-induced immune-suppression in the development of early-onset prostate cancer, we observed significant up-regulation of CTLA4 and IDO1/TDO2 pathways in tumors of the young cohort. Moreover, over-expression of CTLA4 and IDO1 was significantly associated with biochemical recurrence. Our results provide clues on the mechanisms of tumor development and point to potential biomarkers for early detection and treatment for prostate cancer in young men.


Assuntos
Biomarcadores Tumorais/biossíntese , Antígeno CTLA-4/biossíntese , Indolamina-Pirrol 2,3,-Dioxigenase/biossíntese , Neoplasias da Próstata/genética , Adulto , Fatores Etários , Idoso , Biomarcadores Tumorais/genética , Antígeno CTLA-4/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/biossíntese , Neoplasias da Próstata/patologia , Transdução de Sinais/genética
17.
Oncotarget ; 7(18): 26670-9, 2016 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-27050369

RESUMO

To examine the relationship between cytotoxic T lymphocyte antigen-4 (CTLA-4) expression and esophageal carcinoma prognosis, CTLA-4 expression was immunohistochemically detected in paraffin-embedded primary tumor specimens from 158 patients with esophageal cancer. CTLA-4 was detected in the cytoplasm and cell membranes of esophageal cancer cells and in interstitial lymphocytes. In univariate analyses (log-rank), higher interstitial CTLA-4+ lymphocyte density and higher tumor CTLA-4 expression were associated with shorter overall survival (OS). After controlling for age and clinical stage, multivariate analysis (Cox) found that tumor CTLA-4 expression was an independent predictor of shorter OS (HR 2.016, P = 0.004). These results indicate that CTLA-4 expression in the tumor environment (both lymphocytes and tumor cells) is associated with poorer prognosis. In addition, CTLA-4 profiles may be useful for predicting the benefits and toxicity of CTLA-4 blockade in patients with esophageal carcinoma.


Assuntos
Biomarcadores Tumorais/análise , Antígeno CTLA-4/biossíntese , Carcinoma de Células Escamosas/patologia , Neoplasias Esofágicas/patologia , Adulto , Idoso , Antígeno CTLA-4/análise , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/mortalidade , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/mortalidade , Carcinoma de Células Escamosas do Esôfago , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Microambiente Tumoral/fisiologia
18.
Cytokine ; 83: 127-135, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27108398

RESUMO

OBJECTIVES: T-cell repertoire dysfunction characterizes human immunodeficiency virus type 1 (HIV-1) infection, but the pathogenic mechanisms remain unclear. Disease progression is probably due to a profound dysregulation of Th1, Th2, Th17 and Treg patterns. The aim of this study was to analyze the features of CD4+ T cells in HIV-positive patients with different viroimmunological profile. METHODS: we used a gene expression dataset of CD4+ T cells from healthy donors, HIV+ naive patients and Elite Controllers (EC), obtained from the NCBI Gene Expression Omnibus (GEO, http://www.ncbi.nlm.nih.gov/geo/, accession number GSE18233). RESULTS: Principal Component Analysis (PCA) showed an almost complete overlap between the HIV-infected and EC patients, which cannot easily explain the different responses to HIV infection of these two group of patients. We have found that HIV patients and the EC showed an upregulation of the Th1 pro-inflammatory cytokines and chemokines, compared to the controls. Also, we have surprisingly identified IL28B, which resulted downregulated in HIV and EC compared to healthy controls. We focused attention also on genes involved in the constitution of the immunological synapse and we showed that HLA class I and II genes resulted significantly upregulated in HIV and in EC compared to the control. In addition to it, we have found the upregulation of others syncytial molecules, including LAG3, CTLA4, CD28 and CD3, assisting the formation of syncytia with APC cells. CONCLUSIONS: Understanding the mechanisms of HIV-associated immunological chaos is critical to strategically plan focused interventions.


Assuntos
Doadores de Sangue , Linfócitos T CD4-Positivos/metabolismo , Regulação da Expressão Gênica , Infecções por HIV/metabolismo , HIV-1 , Adulto , Antígenos CD/biossíntese , Antígenos CD28/biossíntese , Complexo CD3/biossíntese , Antígeno CTLA-4/biossíntese , Feminino , Antígenos de Histocompatibilidade Classe I/biossíntese , Antígenos de Histocompatibilidade Classe II/biossíntese , Humanos , Masculino
19.
Oncotarget ; 7(11): 13060-8, 2016 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-26918337

RESUMO

The expression levels of CTLA-4 and CD28 were analyzed in 191 nasopharyngeal carcinoma (NPC) patients diagnosed and treated at our hospital between January 2010 and November 2011. The 3-year overall survival (OS) rate (91.4% vs. 81.2%,p = 0.043), failure-free survival (FFS) rate (82.8% vs. 68.0%, p = 0.009) and distant failure-free survival (D-FFS) rate (85.8% vs. 72.3%, p = 0.006) in the low tumor CTLA-4 expression group was higher than in the high tumor CTLA-4 group. There were no differences between the locoregional failure-free survival (LR-FFS) rates in the high and low tumor CTLA-4 expression groups. Moreover, no differences in the OS, FFS, D-FFS, or LR-FFS were observed between the groups with high and low lymphocyte CTLA-4 levels, high and low tumor CD28 levels, or high and low lymphocyte CD28 levels. Cox regression analysis confirmed the prognostic value of tumor CTLA-4 expression, particularly for D-FFS, in NPC patients (p = 0.044). NPC patients with high tumor CTLA-4 expression had a poorer prognosis than those with low expression.


Assuntos
Biomarcadores Tumorais/análise , Antígeno CTLA-4/biossíntese , Carcinoma/patologia , Neoplasias Nasofaríngeas/patologia , Adulto , Idoso , Antígenos CD28/análise , Antígenos CD28/biossíntese , Antígeno CTLA-4/análise , Carcinoma/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/mortalidade , Prognóstico , Taxa de Sobrevida , Adulto Jovem
20.
Clin Cancer Res ; 22(12): 2885-96, 2016 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-26873960

RESUMO

PURPOSE: Recurrent malignant glioma carries a dismal prognosis, and novel therapies are needed. We examined the feasibility and safety of vaccination with irradiated autologous glioma cells mixed with irradiated GM-K562 cells in patients undergoing craniotomy for recurrent malignant glioma. EXPERIMENTAL DESIGN: We initiated a phase I study examining the safety of 2 doses of GM-K562 cells mixed with autologous cells. Primary endpoints were feasibility and safety. Feasibility was defined as the ability for 60% of enrolled subjects to initiate vaccination. Dose-limiting toxicity was assessed via a 3+3 dose-escalation format, examining irradiated tumor cells mixed with 5 × 10(6) GM-K562 cells or 1 × 10(7) GM-K562 cells. Eligibility required a priori indication for resection of a recurrent high-grade glioma. We measured biological activity by measuring delayed type hypersensitivity (DTH) responses, humoral immunity against tumor-associated antigens, and T-lymphocyte activation. RESULTS: Eleven patients were enrolled. Sufficient numbers of autologous tumor cells were harvested in 10 patients, all of whom went on to receive vaccine. There were no dose-limiting toxicities. Vaccination strengthened DTH responses to irradiated autologous tumor cells in most patients, and vigorous humoral responses to tumor-associated angiogenic cytokines were seen as well. T-lymphocyte activation was seen with significantly increased expression of CTLA-4, PD-1, 4-1BB, and OX40 by CD4(+) cells and PD-1 and 4-1BB by CD8(+) cells. Activation was coupled with vaccine-associated increase in the frequency of regulatory CD4(+) T lymphocytes. CONCLUSIONS: Vaccination with irradiated autologous tumor cells mixed with GM-K562 cells is feasible, well tolerated, and active in patients with recurrent malignant glioma. Clin Cancer Res; 22(12); 2885-96. ©2016 AACR.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/uso terapêutico , Glioblastoma/terapia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/biossíntese , Ligante 4-1BB/biossíntese , Adulto , Idoso , Antígeno CTLA-4/biossíntese , Vacinas Anticâncer/efeitos adversos , Vacinas Anticâncer/imunologia , Linhagem Celular Tumoral , Feminino , Humanos , Células K562 , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/terapia , Transplante de Neoplasias/métodos , Ligante OX40/biossíntese , Receptor de Morte Celular Programada 1/biossíntese , Transplante Autólogo , Vacinação
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