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1.
Medicine (Baltimore) ; 99(1): e18462, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31895778

RESUMO

Proinflammatory interleukin-26 (IL-26) is involved in chronic inflammation; however, the role of IL-26 in chronic hepatitis B (CHB) remains unknown.In this study, serum IL-26 was quantified in a cohort of CHB patients at baseline and during telbivudine (LdT) treatment.Our results showed that the serum IL-26 level was significantly elevated in CHB patients compared with that in healthy controls and was time-dependently decreased during LdT treatment, accompanying hepatitis B e antigen (HBeAg) seroconversion and reduced serum levels of hepatitis B virus (HBV) DNA, aspartate transaminase, and alanine transaminase across baseline and treatment. In addition, the serum level of IL-26 exhibited a similar declining trend to that of T helper 17 (Th17) cell-secreted IL-17 during LdT treatment in CHB patients. The percentage of IL-26-expressing CD4 cells was significantly higher than that of IL-26-expressing CD4 cells isolated from the peripheral blood mononuclear cells of CHB patients, suggesting that serum IL-26 might be mainly released from CD4 T cells. Furthermore, the baseline mRNA levels of IL-26 and orphan nuclear receptor RORγt-an important transcription factor expressed by Th17 cells-were positively correlated and displayed the same declining trend across the baseline and LdT treatment in CHB patients, suggesting that Th17 cells could be a possible cellular source of the increased serum IL-26 in CHB patients.Taken together, our results suggest that serum IL-26, possibly produced by Th17 CD4 cells, is a novel and potential biomarker for CHB prognosis and treatment.


Assuntos
Vírus da Hepatite B/imunologia , Hepatite B Crônica/sangue , Hepatite B Crônica/imunologia , Interleucinas/sangue , Adulto , Antivirais/uso terapêutico , Linfócitos T CD4-Positivos/imunologia , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Feminino , Hepatite B Crônica/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Telbivudina/uso terapêutico , Células Th17/imunologia , Adulto Jovem
2.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(11): 1008-1013, 2019 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-31878997

RESUMO

Objective To explore the role of extracellular secretory protein sulfatase-1 (SULF1) in colon cancer prognosis and immune cell infiltration. Methods SULF1 gene expression level in tumor and normal tissues was identified via Oncomine database and Tumor Immune Estimation Resource (Timer) site. The correlation between SULF1 gene expression level and colon cancer prognosis was obtained by Prognoscan database and Gene Expression Profiling Interactive Analysis (GEPIA). The relationship for SULF1 geneexpression level in colon cancer immune cell infiltration and tumor-associated macrophage surface markers was retrieved by Timer database gene module and gene correlation module. The results were further verified by GEPIA database. Results The results of Timer and Oncomine database analysis indicated that SULF1 was highly expressed in colon cancer. The results of Prognoscan chip GSE17536 and GEPIA database showed that the high expression of SULF1 was positively correlated with the poor prognosis of colon cancer. SULF1 was positively correlated with the infiltration of colon cancer immune cells CD8+ T cells, CD4+ T cells, macrophages, neutrophils and dendritic cells, and not associated with B cells. SULF1 had the strongest positive correlation with macrophages (r=0.628), and the correlation with M2-type macrophages was significantly higher than that with M1-type macrophages. Conclusion SULF1 is highly expressed and positively correlated with poor prognosis in colon cancer. The tumor-associated macrophage infiltration may be one of involved mechanisms.


Assuntos
Neoplasias do Colo/metabolismo , Sulfotransferases/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Neoplasias do Colo/diagnóstico , Perfilação da Expressão Gênica , Humanos , Macrófagos/imunologia , Prognóstico
3.
Anticancer Res ; 39(11): 5911-5918, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704815

RESUMO

BACKGROUND/AIM: Double-negative T (DNT) cells are phenotypically CD3+CD4-CD8-T cells. This study aimed to investigate the anti-cancer activity of DNT cells against pancreatic cancer cells. MATERIALS AND METHODS: DNT cells were isolated from human peripheral blood. The effect of DNT cells on proliferation and invasion of the human pancreatic cell line Panc-1 was assessed. Expression of Nrf2 and Fas in Panc-1 cells co-cultured with DNT cells was analyzed with RT-PCR. The supernatants of Panc-1 and DNT co-cultures were analyzed with ELISA for IFN-r and FasL levels. RESULTS: The isolated DNT cell phenotype was CD4-CD8-CD56- CD3+TCR (T cell receptor) α/ß+ T cells with more than 90% purity. Panc-1 cell proliferation was significantly inhibited by co-culture with DNT cells. Panc-1 cells co-cultured with DNT cells showed significantly reduced cell invasion. Panc-1 cells co-cultured with DNT cells showed increased Nrf2 and Fas mRNA expression. Increased INF-r and FasL levels were detected in the supernatants of co-cultures of DNT and pancreatic cells. CONCLUSION: DNT cells inhibited proliferation and invasion of human pancreatic cancer cells. The INF-r, Fas/FasL pathway and Nrf2 may be involved in the anti-cancer effect of DNT cells against human pancreatic cancer.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Técnicas de Cocultura/métodos , Ativação Linfocitária/imunologia , Neoplasias Pancreáticas/prevenção & controle , Apoptose , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Proliferação de Células , Proteína Ligante Fas/metabolismo , Humanos , Fator 2 Relacionado a NF-E2/metabolismo , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Receptores de Interferon/metabolismo , Células Tumorais Cultivadas , Receptor fas/metabolismo
4.
Cancer Immunol Immunother ; 68(12): 2015-2027, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31705171

RESUMO

The transformation and progression of myelodysplastic syndromes (MDS) to secondary acute myeloid leukemia (sAML) involve genetic, epigenetic, and microenvironmental factors. Driver mutations have emerged as valuable markers for defining risk groups and as candidates for targeted treatment approaches in MDS. It is also evident that the risk of transformation to sAML is increased by evasion of adaptive immune surveillance. This study was designed to explore the immune microenvironment, immunogenic tumor-intrinsic mechanisms (HLA and PD-L1 expression), and tumor genetic features (somatic mutations and altered karyotypes) in MDS patients and to determine their influence on the progression of the disease. We detected major alterations of the immune microenvironment in MDS patients, with a reduced count of CD4+ T cells, a more frequent presence of markers related to T cell exhaustion, a more frequent presence of myeloid-derived suppressor cells (MDSCs), and changes in the functional phenotype of NK cells. HLA Class I (HLA-I) expression was normally expressed in CD34+ blasts and during myeloid differentiation. Only two out of thirty-six patients with homozygosity for HLA-C groups acquired complete copy-neutral loss of heterozygosity in the HLA region. PD-L1 expression on the leukemic clone was also increased in MDS patients. Finally, no interplay was observed between the anti-tumor immune microenvironment and mutational genomic features. In summary, extrinsic and intrinsic immunological factors might severely impair immune surveillance and contribute to clonal immune escape. Genomic alterations appear to make an independent contribution to the clonal evolution and progression of MDS.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Células Matadoras Naturais/imunologia , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicas/genética , Células Supressoras Mieloides/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/metabolismo , Carcinogênese , Senescência Celular , Progressão da Doença , Feminino , Antígenos HLA-C/genética , Humanos , Vigilância Imunológica , Masculino , Pessoa de Meia-Idade , Mutação/genética , Evasão Tumoral , Microambiente Tumoral/imunologia , Adulto Jovem
5.
Life Sci ; 237: 116930, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31610190

RESUMO

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by symptoms that include social communication impairments, interaction deficits, and repetitive and stereotyped behaviors. Recent studies have suggested that imbalanced cytokine levels are associated with impaired behavioral outcomes in individuals with ASD. VGX-1027 is a potent immunomodulatory compound that has shown promise for the treatment of several neuroinflammatory disorders. Here, we studied the effects of VGX-1027 on BTBR T+ Itpr3tf/J (BTBR) mice, an animal model of autism. BTBR mice exhibit most of the core behavioral features of ASD, such as reduced sociability and increased repetitive behaviors. In this study, we investigated the effects of VGX-1027 on self-grooming, marble burying and sociability tests using BTBR mice. We further examined its effect on IL-1ß, IL-6, IL-10, TNF-α, IFN-γ, and NF-κB p65 production in splenic CD4+ cells and on IL-1ß, IL-6, IL-10, TNF-α, IFN-γ, COX-2, and iNOS (NOS2) protein and mRNA expression in brain tissues. The administration of VGX-1027 was found to attenuate self-grooming and marble burying behaviors, and enhance social interactions in BTBR mice. Additionally, VGX-1027 treatment resulted in a substantial decrease in IL-1ß, IL-6, TNF-α, IFN-γ, and NF-κB p65 production, but increased IL-10 production in CD4+ T cells. Moreover, this agent was also found to significantly decrease IL-1ß, IL-6, TNF-α, IFN-γ, COX-2, and NOS2 levels and increase IL-10 expression at the protein and mRNA level in brain tissues. Based on results using BTBR mice, our data provide the first evidence that VGX-1027 could potentially be used for the amelioration of autism-like symptoms.


Assuntos
Acetatos/farmacologia , Transtorno Autístico/prevenção & controle , Comportamento Animal/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Mediadores da Inflamação/metabolismo , Inflamação/prevenção & controle , Receptores de Inositol 1,4,5-Trifosfato/fisiologia , Oxazóis/farmacologia , Animais , Transtorno Autístico/etiologia , Transtorno Autístico/metabolismo , Transtorno Autístico/patologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais
6.
Medicine (Baltimore) ; 98(39): e17311, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31574860

RESUMO

Immune infiltration of nasopharyngeal carcinoma (NPC) is closely associated with the patients' prognosis. However, previous studies have not interpreted the difference of infiltrating immune cells in NPC.We comprehensively analyzed the tumor-infiltrating immune cells present in NPC for the first time, which was based on a scientific deconvolution algorithm (CIBERSORT) and the gene expression data of GSE64634. The fractions of 22 immune cells were assessed to reveal the associations between normal samples and NPC samples.Profiles of immune infiltration vary significantly between normal samples and NPC samples, and the variation could characterize the individual differences. NPC samples contained a higher proportion for M1 macrophages, whereas memory B cells and CD4 memory resting T cells were relatively lower.Our data suggest that the differences in the infiltrating immune cells in NPC and these differences would probably facilitate patient consultation and individualized treatment.


Assuntos
Linfócitos do Interstício Tumoral , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Adulto , Algoritmos , Linfócitos B/imunologia , Linfócitos B/patologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , China , Correlação de Dados , Feminino , Expressão Gênica , Humanos , Memória Imunológica , Linfócitos do Interstício Tumoral/classificação , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Macrófagos/imunologia , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/diagnóstico , Carcinoma Nasofaríngeo/imunologia , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/diagnóstico , Neoplasias Nasofaríngeas/imunologia , Neoplasias Nasofaríngeas/patologia , Prognóstico , Reprodutibilidade dos Testes
7.
J Agric Food Chem ; 67(42): 11665-11674, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31588753

RESUMO

A long-term high-fat diet (HFD) can cause a range of health problems. Gut microbiota plays a decisive role in the development of HFD-associated inflammation, involved in function of T cells. This study was designed to probe the regulative effects of dietary stachyose, a functional oligosaccharide, on HFD-induced weight gain, inflammation, gut microbiota dysbiosis, and T cell abnormality in C57Bl/6 mice. Mice were divided into three groups which received normal chow, HFD and HFD plus stachyose (400 mg/kg), respectively. Results showed that administration of stachyose diminished the HFD-induced upregulation of serum TNF-α level and elevation of peripheral blood leukocyte populations to alleviate the HFD-caused colonic and hepatic inflammation in mice. Analysis of gut microbiota revealed that stachyose improved the intestinal homeostasis of HFD-fed mice by improving the bacterial diversity with the increases in the relative abundances of the Prevotellaceae_NK3B31_group, Parasutterella, Christensenellaceae_R-7_group, and Anaerovorax, as well as the fecal level of butanoic acid, while decreasing the ratio of Firmicutes-to-Bacteroidetes and the abundances of the Lachnospiraceae_NK4A136_group, Desulfovibrio, Anaerotruncus, Mucispirillum, Roseburia, and Odoribacter. Flow cytometric analysis showed that stachyose antagonized the HFD-induced decrease of peripheral CD4+ T cell population in mice. Conclusively, these findings suggest that long-term consumption of stachyose can ameliorate the HFD-associated colonic and hepatic inflammation and its complications by modulating gut microbiota.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Colo/imunologia , Disbiose/dietoterapia , Microbioma Gastrointestinal , Fígado/imunologia , Oligossacarídeos/metabolismo , Animais , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Colo/microbiologia , Dieta Hiperlipídica/efeitos adversos , Disbiose/imunologia , Disbiose/microbiologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL
8.
Nature ; 574(7779): 565-570, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31645726

RESUMO

Co-inhibitory immune receptors can contribute to T cell dysfunction in patients with cancer1,2. Blocking antibodies against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1) partially reverse this effect and are becoming standard of care in an increasing number of malignancies3. However, many of the other axes by which tumours become inhospitable to T cells are not fully understood. Here we report that V-domain immunoglobulin suppressor of T cell activation (VISTA) engages and suppresses T cells selectively at acidic pH such as that found in tumour microenvironments. Multiple histidine residues along the rim of the VISTA extracellular domain mediate binding to the adhesion and co-inhibitory receptor P-selectin glycoprotein ligand-1 (PSGL-1). Antibodies engineered to selectively bind and block this interaction in acidic environments were sufficient to reverse VISTA-mediated immune suppression in vivo. These findings identify a mechanism by which VISTA may engender resistance to anti-tumour immune responses, as well as an unexpectedly determinative role for pH in immune co-receptor engagement.


Assuntos
Antígenos B7/química , Antígenos B7/metabolismo , Glicoproteínas de Membrana/metabolismo , Linfócitos T/metabolismo , Animais , Anticorpos Bloqueadores/imunologia , Anticorpos Bloqueadores/farmacologia , Antígenos B7/antagonistas & inibidores , Antígenos B7/imunologia , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Cristalografia por Raios X , Epitopos de Linfócito B/química , Epitopos de Linfócito B/imunologia , Feminino , Histidina/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Ligantes , Masculino , Glicoproteínas de Membrana/imunologia , Camundongos , Modelos Moleculares , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Ligação Proteica/efeitos dos fármacos , Domínios Proteicos , Linfócitos T/citologia , Linfócitos T/imunologia , Microambiente Tumoral/imunologia
9.
Cancer Immunol Immunother ; 68(12): 1921-1934, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31637475

RESUMO

Blockade of the PD-1/PD-L1 pathway with targeted monoclonal antibodies has demonstrated encouraging anti-tumour activity in multiple cancer types. We present the case of a patient with BRAF-negative stage IVC anaplastic thyroid cancer (ATC) treated with the anti-PD-1 monoclonal antibody, pembrolizumab, following radiographic progression on chemoradiation. Blood samples were collected prior to and at four time points during treatment with pembrolizumab. Mass cytometry was used to determine expression of relevant biomarkers by peripheral blood mononuclear cells. Faecal samples were collected at baseline and 4 weeks following treatment initiation; taxonomic profiling using 16S ribosomal RNA (rRNA) gene sequencing was performed. Following treatment, a marked expansion in CD20+ B cell, CD16+ CD56lo NK cell and CD45RO+ CCR7+ central memory CD4+ T-cell populations was observed in the peripheral blood. Proportions of cells expressing the co-receptors TIGIT, OX40 and CD86 also increased during treatment. A high abundance of bacteria of the order Bacteroidales, specifically from the Bacteroidaceae and Rikenellaceae families, was identified in the faecal microbiota. Moreover, the patient's microbiome was enriched in Clostridiales order members Ruminococcaceae, Veillonellaceae and Lachnospiraceae. Alpha diversity of the gut microbiome was significantly higher following initiation of checkpoint therapy as assessed by the Shannon and Simpson index. Our results suggest that treatment with pembrolizumab promotes expansion of T-, B- and NK cell populations in the peripheral blood at the time of tumour regression and have the potential to be implemented as predictive biomarkers in the context of checkpoint blockade therapy. Larger studies to confirm these findings are warranted.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Fezes/microbiologia , Células Matadoras Naturais/imunologia , Carcinoma Anaplásico da Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Bacteroides , Humanos , Masculino , Microbiota , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/antagonistas & inibidores , RNA Ribossômico 16S/análise
10.
Nutr. hosp ; 36(5): 1205-1212, sept.-oct. 2019. tab, graf
Artigo em Inglês | IBECS | ID: ibc-184646

RESUMO

Introduction: much evidence confirms that vitamin D may be associated with an improvement in CD4 cell counts in HIV-infected individuals, where antiretroviral therapy (ART) is used and associated with decreased 25(OH)D levels. Objective: to carry out a systematic review on the effect of vitamin D supplementation on HIV-infected adult patients. Methods: the research was conducted in the databases Science Direct, PubMed, BVS, Scielo Cochrane and Periods, from February to April 2018, with publication limit from 2000 to 2018, without restriction of gender, ethnicity and involving individuals with age older than 18 years. To evaluate the quality of the studies, we used the protocol Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) and the Jadad scale. Results: the search initially resulted in 198 articles. After the selection process 5 articles were identified as eligible, where they highlight that vitamin D supplementation may be an associated and effective intervention to reduce hypovitaminosis. ART reduces vitamin D3 levels and changes its metabolism, being associated with the risk of mortality. However, adequate levels of 25(OH)D are positively associated with the number of CD4 + cells and the reduction of infection levels. Conclusion: vitamin D supplementation promotes immune recovery. However, the cases analysed were few, insufficient to fully confirm the benefits and recommend supplementation. Therefore, intervention studies are needed to elucidate the role of vitamin D in human protection against HIV infections


Introducción: muchas evidencias ratifican que la vitamina D puede estar asociada con la mejora de los niveles de células CD4 en individuos infectados por el VIH, tratados con terapia antirretroviral (ART) que se asocia a la disminución de los niveles de 25(OH)D. Objetivo: realizar una revisión sistemática sobre el efecto de la suplementación de vitamina D en pacientes adultos infectados con VIH. Métodos: la investigación fue realizada en las bases de datos Science Direct, PubMed, BVS, Scielo Cochrane y periódicos, de febrero a abril de 2018, con límite de publicación de 2000 a 2018, sin restricción de género, etnicidad y que involucra a individuos con edad mayores de 18 años. Para la evaluación de la calidad de los estudios, se utilizó el protocolo Preferred Reporting Items for Systematic Reviews y Meta-Analyzes (PRISMA) y la escala de Jadad. Resultados: la encuesta inicialmente resultó en 198 artículos. Después del proceso de selección, 5 artículos fueron identificados como elegibles, donde ponen de manifiesto que la suplementación con vitamina D puede ser una intervención asociada y eficaz para reducir la hipovitaminosis. La ART reduce niveles de la vitamina D3 y altera su metabolismo, estando asociada al riesgo de mortalidad. Sin embargo, los niveles adecuados de 25(OH)D están asociados positivamente al número de células CD4 + y la reducción de los niveles de infecciones. Conclusión: la suplementación de vitamina D promueve la recuperación inmunológica. Sin embargo, los casos analizados fueron pocos, insuficientes para confirmar totalmente los beneficios y recomendar la suplementación. Por lo tanto, estudios de intervención son necesarios para elucidar la actuación de la vitamina D en la protección humana contra las infecciones por el VIH


Assuntos
Humanos , Colecalciferol/administração & dosagem , Colecalciferol/metabolismo , Infecções por HIV/dietoterapia , Infecções por HIV/imunologia , Linfócitos T CD4-Positivos/imunologia , Reconstituição Imune
11.
Cancer Immunol Immunother ; 68(10): 1561-1572, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31494742

RESUMO

Preclinical and clinical studies have suggested that cancer treatment with antitumor antibodies induces a specific adaptive T cell response. A central role in this process has been attributed to CD4+ T cells, but the relevant T cell epitopes, mostly derived from non-mutated self-antigens, are largely unknown. In this study, we have characterized human CD20-derived epitopes restricted by HLA-DR1, HLA-DR3, HLA-DR4, and HLA-DR7, and investigated whether T cell responses directed against CD20-derived peptides can be elicited in human HLA-DR-transgenic mice and human samples. Based on in vitro binding assays to recombinant human MHC II molecules and on in vivo immunization assays in H-2 KO/HLA-A2+-DR1+ transgenic mice, we have identified 21 MHC II-restricted long peptides derived from intracellular, membrane, or extracellular domains of the human non-mutated CD20 protein that trigger in vitro IFN-γ production by PBMCs and splenocytes from healthy individuals and by PBMCs from follicular lymphoma patients. These CD20-derived MHC II-restricted peptides could serve as a therapeutic tool for improving and/or monitoring anti-CD20 T cell activity in patients treated with rituximab or other anti-CD20 antibodies.


Assuntos
Antígenos CD20/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfoma/tratamento farmacológico , Animais , Feminino , Cadeias HLA-DRB1/imunologia , Humanos , Interferon gama/biossíntese , Linfoma/imunologia , Camundongos , Rituximab/uso terapêutico
12.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(7): 577-582, 2019 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-31537240

RESUMO

Objective To investigate the roles of Th1 cytokines tumor necrosis factor α (TNF-α), interferon gamma (IFN-γ) and multifunctional T cells in nucleotides binding oligomer domain 2 knockout (NOD2-/-) mice infected with Mycobacterium tuberculosis (MTB) H37Ra. Methods Mouse models of pulmonary infection were established by tracheal instillation of MTB strain H37Ra into NOD2-/- mice and C57BL/6 mice (n=10 each group). Lung tissues were removed and stained by HE staining and pathological scores were evaluated 4 weeks after infection. The levels of TNF-α and IFN-γ in the lung homogenates were detected by ELISA, and the ratio of multifunctional CD4+ T and CD8+ T cells in the spleen were examined by flow cytometry. Results MTB infection promoted lung inflammation of NOD2-/- mice. The levels of TNF-α and IFN-γ in the lung tissues of NOD2-/- mice increased. Compared with normal saline group, TNF-α+, IFN-γ+ cells and TNF-α+IFN-γ+ cells in CD4+/CD8+T cells significantly increased in NOD2-/- mice and C57BL/6 mice after the infection. TNF-α+CD4+T cells, IFN-γ+CD4+T cells and IFN-γ+CD8+T cells in MTB-infected NOD2-/- mice were significantly higher than those in MTB-infected C57BL/6 mice. Conclusion H37Ra can induce Th1 immune response in NOD2-/- mice.


Assuntos
Mycobacterium tuberculosis , Células Th1/imunologia , Tuberculose/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Interferon gama/imunologia , Pulmão/imunologia , Pulmão/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Adaptadora de Sinalização NOD2/genética , Baço/citologia , Baço/imunologia , Fator de Necrose Tumoral alfa/imunologia
13.
Cancer Immunol Immunother ; 68(11): 1865-1873, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31448380

RESUMO

It is well recognized that CD4+ T cells may play an important role in immunosurveillance and immunotherapy against cancer. However, the details of how these cells recognize and eliminate the tumor cells remain incompletely understood. For the past 25 years, we have focused on how CD4+ T cells reject multiple myeloma cells in a murine model (MOPC315). In our experimental system, the secreted tumor-specific antigen is taken up by tumor-infiltrating macrophages that process it and present a neoepitope [a V region-derived idiotypic (Id) peptide] on MHC class II molecules to Th1 cells. Stimulated Th1 cells produce IFNγ, which activates macrophages in a manner that elicits an M1-like, tumoricidal phenotype. Through an inducible nitric oxide synthetase (iNOS)-dependent mechanism, the M1 macrophages secrete nitric oxide (NO) that diffuses into neighboring tumor cells. Inside the tumor cells, NO-derived reactive nitrogen species, including peroxynitrite, causes nitrosylation of proteins and triggers apoptosis by the intrinsic apoptotic pathway. This mode of indirect tumor recognition by CD4+ T cells operates independently of MHC class II expression on cancer cells. However, secretion of the tumor-specific antigen, and uptake and MHCII presentation on macrophages, is required for rejection. Similar mechanisms can also be observed in a B-lymphoma model and in the unrelated B16 melanoma model. Our findings reveal a novel mechanism by which CD4+ T cells kill tumor cells indirectly via induction of intratumoral cytotoxic macrophages. The data suggest that induction of M1 polarization of tumor-infiltrating macrophages, by CD4+ T cells or through other means, could serve as an immunotherapeutic strategy.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Macrófagos/imunologia , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/terapia , Animais , Antígenos de Neoplasias/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Humanos , Imunoterapia/métodos , Camundongos , Células Th1/imunologia
14.
Medicine (Baltimore) ; 98(30): e16345, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31348233

RESUMO

To evaluate the potential role of Pten and CD4FOXP3 T cells in prognosis from endometrial cancer.Tissue samples and clinical data were collected from 200 patients with endometrial cancer and 100 control patients with benign uterine diseases. The expressions of Pten and CD4FOXP3 T cells were quantified by immunohistochemistry and immunofluorescence. After surgery, all patients were followed up for an average of 56.3 months. Surgical effects were evaluated based on the patients' symptoms and signs. A two-sided P value < .05 was considered significant.Pten diminished and CD4FOXP3 T cells significantly accumulated with the progression of endometial cancer, in comparison to the controls. Moreover, Pten expression was negatively correlated with the count of CD4FOXP3 T cells. Pten and CD4FOXP3 T cells were correlated with clinical characteristics, including tumor stage, differentiation and associated with patients' disease-free survival.Limited data were available between the expressions of Pten and CD4FOXP3 T cells in patients with endometrial cancer. Our study findings suggested that the expressions of Pten and CD4FOXP3 T cells might become possible biomarkers for the diagnosis and prediction in endometrial cancer.


Assuntos
Neoplasias do Endométrio/patologia , Fatores de Transcrição Forkhead/imunologia , PTEN Fosfo-Hidrolase/biossíntese , Linfócitos T/imunologia , Adulto , Idoso , Biomarcadores Tumorais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Estudos de Casos e Controles , Neoplasias do Endométrio/genética , Feminino , Fatores de Transcrição Forkhead/biossíntese , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/imunologia , Prognóstico , Linfócitos T/metabolismo
15.
Rev Soc Bras Med Trop ; 52: e20190101, 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31340370

RESUMO

INTRODUCTION: Tropical spastic paraparesis/HTLV-1 associated myelopathy (TSP/HAM) is a disease caused by human T-cell lymphotropic virus type 1 (HTLV-I) that mainly infects CD4 T cells-for example, those of the CD4+CD25hiFOXP3+ [Treg] phenotype-where it inhibits forkhead box protein P3 (FOXP3) expression and promotes interferon-γ (IFN-γ) expression. However, the role it exerts on regulatory B cells (CD19+CD24hiCD38hi; Breg) is unknown. METHODS: The frequencies of Treg and Breg cells was evaluated and the Th1 profiles were assessed in TSP/HAM patients and healthy control subjects. RESULTS: Low percentages of Breg cells and high production of IFN-γ were observed in patients compared to those in healthy control subjects. CONCLUSIONS: The low percentage of Breg cells in patients and the increase in the frequency of Th1 cells suggest an imbalance in the control of the inflammatory response that contributes to the immunopathogenesis of TSP/HAM.


Assuntos
Linfócitos B Reguladores/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Interferon gama/imunologia , Paraparesia Espástica Tropical/imunologia , Linfócitos T Reguladores/imunologia , Adolescente , Linfócitos B Reguladores/virologia , Linfócitos T CD4-Positivos/virologia , Linfócitos T CD8-Positivos/virologia , Feminino , Humanos , Masculino , Paraparesia Espástica Tropical/virologia , Linfócitos T Reguladores/virologia , Carga Viral
16.
Scand J Immunol ; 90(5): e12809, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31322747

RESUMO

We evaluated 18 DiGeorge syndrome (DGS) patients and aimed to investigate the immunological changes in this population. DGS patients with low naive CD4+ T and CD8+ T cells were defined as high-risk (HR) patients, whereas patients with normal numbers of naive CD4+ and CD8+ T cells were defined as standard risk (SR) patients. Level of serum IgM, CD3+ T cell counts and percentages of class-switched memory B cells were significantly low in HR group compared to SR ones. Severe infections and persistent hypoparathyroidism were detected significantly higher in HR group. Patients with reduced percentages of class-switched B cells had earlier onset of infection, lower blood IgM, lower CD4+ and CD8+ T counts than patients with normal class-switched memory B cells. Decreased levels of IgM were associated with low numbers of naive CD4+ and recent thymic emigrants T cells. Monitoring the immune changes of patients with DGS would be useful to predict the severe phenotype of disease.


Assuntos
Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Síndrome de DiGeorge/imunologia , Imunoglobulina M/sangue , Adolescente , Adulto , Criança , Pré-Escolar , Síndrome de DiGeorge/genética , Feminino , Humanos , Hipoparatireoidismo/diagnóstico , Switching de Imunoglobulina/imunologia , Memória Imunológica/imunologia , Lactente , Contagem de Linfócitos , Masculino
17.
Scand J Immunol ; 90(5): e12808, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31322752

RESUMO

CD4+ T cell immunotherapy has potential for treatment in HIV-infected patients. A large number of expanded CD4+ T cells and confirmation of functional-related phenotypes are required for ensuring the successful outcomes of treatment. Freshly isolated CD4+ T cells from healthy donors were activated with anti-CD3/28-coated magnetic beads at different bead-to-cell ratios and cultured in the absence and presence of IL-2 supplementation for 3 weeks. Fold expansion, cell viability, growth kinetic and lymphocyte subset identities were determined. Data demonstrated that a 1:1 bead-to-cell ratio rendered the highest expansion of 1044-fold with 88% viability and 99.5% purity followed by the 2:1 and 0.5:1 ratios. No significant difference in proliferation and phenotypes was found between non-IL-2 and IL-2 supplementation groups. Several specific surface molecule expressions of the expanded cells including chemokine receptors, adhesion molecules, co-stimulatory molecules, activation molecules, maturation markers, cytokine receptors and other molecules were altered when compared to the unexpanded cells. This optimized expansion protocol using the 1:1 bead-to-cell ratio of anti-CD3/28-coated magnetic beads and culture condition without IL-2 supplementation provided the satisfactory yield with good reproducibility. Specific surface molecule expressions of the expanded cells presented potential roles in proliferation, differentiation, homeostasis, apoptosis and organ homing.


Assuntos
Antígenos CD28/imunologia , Complexo CD3/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/transplante , Infecções por HIV/terapia , Imunoterapia Adotiva/métodos , Nanopartículas de Magnetita/uso terapêutico , Adulto , Proliferação de Células , Células Cultivadas , Materiais Revestidos Biocompatíveis , Humanos , Interleucina-2/imunologia , Ativação Linfocitária/imunologia , Resultado do Tratamento
18.
BMC Infect Dis ; 19(1): 588, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31277590

RESUMO

BACKGROUND: HIV controllers (HICs) are a rare group of HIV-1-infected individuals able to naturally control viral replication. Several studies have identified the occurrence of HIV dual infections in seropositive individuals leading to disease progression. In HICs, however, dual infections with divergent outcomes in pathogenesis have been described. CASE PRESENTATION: Here, we present a case report of a HIC diagnosed in late 1999 who displayed stable CD4+ T cell levels and low plasmatic viral load across 12 years of follow-up. In early 2013, the patient started to present an increase in viral load, reaching a peak of 10,000 copies/ml in early 2014, followed by an oscillation of viremia at moderate levels in the following years. The genetic diversity of env proviral quasispecies from peripheral blood mononuclear cells (PBMCs) was studied by single genome amplification (SGA) at six timepoints across 2009-2017. Phylogenetic analyses of env sequences from 2009 and 2010 samples showed the presence of a single subtype B variant (called B1). Analyses of sequences from 2011 and after revealed an additional subtype B variant (called B2) and a subsequent dominance shift in the proviral quasispecies frequencies, with the B2 variant becoming the most frequent from 2014 onwards. Latent syphilis related to unprotected sexual intercourse was diagnosed a year before the first detection of B2, evidencing risk behavior and supporting the superinfection hypothesis. Immunologic analyses revealed an increase in CD8+ and CD4+ T cell immune activation following viremia increase and minor T cell subset alterations during follow-up. HIV-specific T cell responses remained low throughout the follow-up period. CONCLUSIONS: Altogether, these results show that loss of viremia control in the HIC was associated with superinfection. These data alert to the negative consequences of reinfection on HIV pathogenesis, even in patients with a long history of viremia control and an absence of disease progression, reinforcing the need for continued use of adequate prevention strategies.


Assuntos
Infecções por HIV/virologia , HIV-1/fisiologia , Superinfecção/virologia , Replicação Viral/fisiologia , Adulto , Fármacos Anti-HIV/uso terapêutico , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/virologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Feminino , Seguimentos , Infecções por HIV/tratamento farmacológico , HIV-1/isolamento & purificação , HIV-1/patogenicidade , Antígenos HLA-B/genética , Humanos , Leucócitos Mononucleares/virologia , Masculino , Filogenia , RNA Viral/sangue , Sífilis/diagnóstico , Carga Viral , Viremia/tratamento farmacológico , Viremia/virologia
19.
Nat Commun ; 10(1): 3000, 2019 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-31278254

RESUMO

Tumor-driven immune suppression is a major barrier to successful immunotherapy in ovarian carcinomas (OvCa). Among various mechanisms responsible for immune suppression, arginase-1 (ARG1)-carrying small extracellular vesicles (EVs) emerge as important contributors to tumor growth and tumor escape from the host immune system. Here, we report that small EVs found in the ascites and plasma of OvCa patients contain ARG1. EVs suppress proliferation of CD4+ and CD8+ T-cells in vitro and in vivo in OvCa mouse models. In mice, ARG1-containing EVs are transported to draining lymph nodes, taken up by dendritic cells and inhibit antigen-specific T-cell proliferation. Increased expression of ARG1 in mouse OvCa cells is associated with accelerated tumor progression that can be blocked by an arginase inhibitor. Altogether, our studies show that tumor cells use EVs as vehicles to carry over long distances and deliver to immune cells a metabolic checkpoint molecule - ARG1, mitigating anti-tumor immune responses.


Assuntos
Arginase/metabolismo , Vesículas Extracelulares/imunologia , Neoplasias Ovarianas/imunologia , Evasão Tumoral/imunologia , Animais , Arginase/antagonistas & inibidores , Arginase/imunologia , Ascite/imunologia , Ascite/patologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Comunicação Celular/imunologia , Linhagem Celular Tumoral/transplante , Proliferação de Células/efeitos dos fármacos , Estudos de Coortes , Conjuntos de Dados como Assunto , Células Dendríticas/imunologia , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Vesículas Extracelulares/metabolismo , Feminino , Humanos , Estimativa de Kaplan-Meier , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Camundongos , Pessoa de Meia-Idade , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia
20.
Cancer Immunol Immunother ; 68(8): 1331-1340, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31317218

RESUMO

Expression of inhibitors of apoptosis protein (IAP) family members is associated with poor prognosis in cancer patients. Immunity to ML-IAP (livin) and survivin has been well studied in patients with a variety of tumors. XIAP, the most potent inhibitor of apoptosis, is widely expressed in melanoma. To better define its potential role as an immunogenic target, cellular and humoral responses to XIAP were investigated in patients with advanced melanoma. An overlapping peptide library covering the full length of the XIAP protein was used to screen T cell responses of peripheral blood mononuclear cells (PBMC) from stage-IV melanoma patients treated with or without anti-CTLA4 (ipilimumab). The screen identified an array of peptides that predominantly induced CD4+ T cell responses. XIAP epitope-specific CD4+ T cells revealed proliferative responses to melanoma cells that express XIAP. Humoral responses to XIAP were also explored. Cellular and humoral responses to XIAP were associated with beneficial clinical outcomes after ipilimumab-based treatment, supporting XIAP as a potential therapeutic target.


Assuntos
Antineoplásicos/uso terapêutico , Linfócitos T CD4-Positivos/imunologia , Epitopos de Linfócito T/imunologia , Imunoterapia/métodos , Ipilimumab/uso terapêutico , Melanoma/imunologia , Fragmentos de Peptídeos/imunologia , Neoplasias Cutâneas/imunologia , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/imunologia , Proliferação de Células , Células Cultivadas , ELISPOT , Humanos , Imunidade Humoral , Ativação Linfocitária , Melanoma/tratamento farmacológico , Estadiamento de Neoplasias , Neoplasias Cutâneas/tratamento farmacológico , Resultado do Tratamento
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