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1.
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
2.
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
3.
Cancer Immunol Immunother ; 68(8): 1359-1368, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31332464

RESUMO

Immune checkpoint inhibitors targeting coinhibitory pathways in T cells possess efficacy in combating cancer. In addition to PD-1/PD-L1 and CTLA-4 antibodies which are already established in tumor immunotherapy, immune checkpoints such as LAG-3 or BTLA are emerging, which may have the potential to enhance T-cell responses alone or in combination with PD-1 blockers. CD4+ T cells play a central role in the immune system and contribute to productive immune responses in multiple ways. The effects of immune checkpoint inhibitors on this cell subset may thus critically influence therapeutic outcomes. Here, we have used in vitro responses to tetanus toxoid (TT) as a model system to study the effects of immune checkpoint inhibitors on CD4+ T-cell responses. CFSE-labeled PBMCs of 65 donors were stimulated with TT in the presence of blocking antibodies to PD-L1, CTLA-4, LAG-3, or BTLA for 7 days. We found that the PD-L1 antibody greatly enhanced cytokine production and antigen-specific CD4+ T-cell proliferation, whereas blocking antibodies to BTLA or LAG-3 did not augment responses to TT. Surprisingly, the presence of the therapeutic CTLA-4 antibody ipilimumab resulted in a significant reduction of CD4+ T-cell proliferation and cytokine production. Stimulation experiments with an IgG4 variant of ipilimumab indicated that the inhibitory effect of ipilimumab was dependent on its IgG1 isotype. Our results indicate that the therapeutic CTLA-4 antibody ipilimumab can impair CD4+ effector T-cell responses and that this activity is mediated by its Fc part and CD16-expressing cells.


Assuntos
Anticorpos Monoclonais/farmacologia , Antineoplásicos/farmacologia , Linfócitos T CD4-Positivos/imunologia , Vacinas Anticâncer/imunologia , Imunoterapia/métodos , Ipilimumab/farmacologia , Neoplasias/terapia , Anticorpos Monoclonais/uso terapêutico , Antígenos CD/imunologia , Antineoplásicos/uso terapêutico , Antígeno B7-H1/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Antígeno CTLA-4/imunologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Citocinas/metabolismo , Humanos , Fragmentos Fc das Imunoglobulinas/metabolismo , Ipilimumab/uso terapêutico , Ativação Linfocitária/efeitos dos fármacos , Neoplasias/imunologia , Receptores Imunológicos/imunologia , Toxoide Tetânico/imunologia
4.
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
5.
J Agric Food Chem ; 67(33): 9382-9389, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31361959

RESUMO

Early stage exposure of foodborne substances, such as brightening agent titanium dioxide nanoparticles (TiO2 NPs), can cause long-term effects in adulthood. We aimed to explore the potential adverse effect of long-term dietary intake of TiO2 NPs. After feeding for 2-3 months from weaning, TiO2 NPs-exposed mice showed lower body weight and induced intestinal inflammation. However, this phenomenon was not observed in gut microbiota-removed mice. TiO2 NPs exposure rarely affected the diversity of microbial communities, but significantly decreased the abundance of several probiotic taxa including Bifidobacterium and Lactobacillus. Additionally, TiO2 NPs aggravated DSS-induced chronic colitis and immune response in vivo, and reduced the population of CD4+T cells, regulatory T cells, and macrophages in mesenteric lymph nodes. Therefore, dietary TiO2 NPs could interfere with the balance of immune system and dynamic of gut microbiome, which may result in low-grade intestinal inflammation and aggravated immunological response to external stimulus, thus introducing potential health risk.


Assuntos
Intestinos/efeitos dos fármacos , Intestinos/imunologia , Nanopartículas/metabolismo , Nanopartículas/toxicidade , Titânio/metabolismo , Titânio/toxicidade , Animais , Bactérias/classificação , Bactérias/efeitos dos fármacos , Bactérias/genética , Bactérias/isolamento & purificação , Peso Corporal/efeitos dos fármacos , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Intestinos/microbiologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Fatores de Tempo
6.
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
7.
Vet Microbiol ; 235: 1-9, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31282365

RESUMO

Oral immunization is a commonly employed route for inducing local immunity. However, the application of oral immunization is limited by the short-term persistence of immunity, particularly for inactivated viruses. The ultimate goal for mucosal vaccination is to stimulate protective immunological memory. In the intestine, long-term persistence of immunity is related to CD4+CD8+ memory T-cells. In this study, piglets were orally immunized with Bacillus subtilis spores (B.s) plus whole inactivated porcine epidemic diarrhea virus (PEDV WIV), followed by booster oral immunization. Initially, the results showed that B.s plus PEDV WIV enhanced the anti-PEDV capability on mucosal surfaces, as evidenced by plaque reduction neutralization tests in serum and intestinal fluid. Elevated antigen-specific IgG titers in the serum and IgA titers in saliva, feces and nasal washing liquid were also observed. Meanwhile, B.s plus PEDV WIV increased the area of Peyer's patches and the number of intraepithelial lymphocytes in the ileum of piglets. Similarly, the percentage of CD4+CD8+ memory T-cells were upregulated and proliferation ability of antigen-specific memory T-cell was strengthened in intestinal mucosal-associated lymphocytes, which was accompanied with increased expression of CCR9 after oral immunization with B.s plus PEDV WIV. In addition, the activation of memory T-cells is correlated with the increased mRNA expression of Toll-like receptor 2 and 4, as well as interleukin-6 and induced by B.s. Collectively, the study provided further insight into the potential immunopotentiator ability of B.s to assist PEDV WIV in the potentiation of immunity by upregulating memory CD4+CD8+ T cells via oral immunization.


Assuntos
Bacillus subtilis/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Memória Imunológica , Mucosa Intestinal/imunologia , Vírus da Diarreia Epidêmica Suína/imunologia , Administração Oral , Animais , Anticorpos Antivirais/sangue , Imunização/métodos , Imunização Secundária , Imunoglobulina G/sangue , Esporos/imunologia , Suínos , Doenças dos Suínos/imunologia , Doenças dos Suínos/prevenção & controle , Regulação para Cima , Vacinas de Produtos Inativados/imunologia
8.
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
9.
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
10.
Anticancer Res ; 39(6): 3039-3046, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31177146

RESUMO

BACKGROUND/AIM: Programmed death-ligand 1 (PD-L1) expression in tumor cells is regulated by a close interrelation between tumor and stromal cells within the tumor microenvironment. Our aim was to evaluate the clinical and biological significance of PD-L1 expression in oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: PD-L1, cluster of differentiation (CD)4, CD8, and forkhead box P3 (FOXP3) expression in tumor tissues obtained from 77 patients with OSCC was evaluated by immunohistochemical staining, and then analyzed for associations with clinical and biological factors. RESULTS: Among the clinicopathological factors tested, only vascular invasion showed a trend toward lower PD-L1 expression (p=0.05). Metabolic tumor volume (MTV), and total lesion glycolysis (TLG) significantly positively correlated with PD-L1 expression (MTV, p=0.04; TLG, p=0.03). In patients with OSCC with high PD-L1 expression, those whose tumors had abundant infiltrating CD4+ T-cells showed a longer progression-free survival than those with low CD4+ T-cell infiltration (p=0.0452). CONCLUSION: As regulation of PD-L1 expression is complex, its evaluation combined with other markers may be useful to determine clinical applications of PD-L1 expression.


Assuntos
Antígeno B7-H1/análise , Biomarcadores Tumorais/análise , Neoplasias Bucais/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Microambiente Tumoral , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD4-Positivos/imunologia , Feminino , Glicólise , Humanos , Imuno-Histoquímica , Linfócitos do Interstício Tumoral/imunologia , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/diagnóstico por imagem , Neoplasias Bucais/metabolismo , Neoplasias Bucais/cirurgia , Tomografia por Emissão de Pósitrons , Intervalo Livre de Progressão , Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico por imagem , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/cirurgia , Fatores de Tempo , Carga Tumoral
11.
Cancer Immunol Immunother ; 68(7): 1195-1209, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31177329

RESUMO

The anti-tumor efficacy of TCR-engineered T cells in vivo depends largely on less-differentiated subsets such as T cells with naïve-like T cell (TN) phenotypes with greater expansion and long-term persistence. To increase these subsets, we compared the generation of New York esophageal squamous cell carcinoma-1 (NY-ESO-1)-specific T cells under supplementation with either IL-2 or IL-7/IL-15. PBMCs were transduced with MS3II-NY-ESO-1-siTCR retroviral vector. T cell generation was adapted from a CD19-specific CART cell production protocol. Comparable results in viability, expansion and transduction efficiency of T cells under stimulation with either IL-2 or IL-7/IL-15 were observed. IL-7/IL-15 led to an increase of CD4+ T cells and a decrease of CD8+ T cells, enriched the amount of TN among CD4+ T cells but not among CD8+ T cells. In a 51Cr release assay, similar specific lysis of NY-ESO-1-positive SW982 sarcoma cells was achieved. However, intracellular cytokine staining revealed a significantly increased production of IFN-γ and TNF-α in T cells generated by IL-2 stimulation. To validate these unexpected findings, NY-ESO-1-specific T cell production was evaluated in another protocol originally established for TCR-engineered T cells. IL-7/IL-15 increased the proportion of TN. However, the absolute number of TN did not increase due to a significantly slower expansion of T cells with IL-7/IL-15. In conclusion, IL-7/IL-15 does not seem to be superior to IL-2 for the generation of NY-ESO-1-specific T cells. This is in sharp contrast to the observations in CD19-specific CART cells. Changes of cytokine cocktails should be carefully evaluated for individual vector systems.


Assuntos
Antígenos de Neoplasias/metabolismo , Engenharia Celular/métodos , Imunoterapia Adotiva/métodos , Proteínas de Membrana/metabolismo , Neoplasias/terapia , Receptores de Antígenos Quiméricos/imunologia , Antígenos CD19/metabolismo , Antígenos de Neoplasias/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/transplante , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/transplante , Técnicas de Cultura de Células/métodos , Linhagem Celular Tumoral , Meios de Cultura , Humanos , Interleucina-15/imunologia , Interleucina-2/imunologia , Interleucina-7/imunologia , Proteínas de Membrana/imunologia , Neoplasias/imunologia , Receptores de Antígenos Quiméricos/genética
12.
Cancer Sci ; 110(8): 2348-2356, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31222843

RESUMO

Immune checkpoint blockade (ICB) therapy has achieved remarkable clinical benefit in non-small-cell lung cancer (NSCLC), but our understanding of biomarkers that predict the response to ICB remain obscure. Here we integrated somatic mutational profile and clinicopathologic information from 113 NSCLC patients treated by ICB (CTLA-4/PD-1). High tumor mutation burden (TMB) and neoantigen burden were identified significantly associated with improved efficacy in NSCLC immunotherapy. Furthermore, we identified apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) mutational signature was markedly associated with responding of ICB therapy (log-rank test, P = .001; odds ratio (OR), 0.18 [95% CI, 0.06-0.50], P < .001). The association with progression-free survival remained statistically significant after controlling for age, sex, histological type, smoking, PD-L1 expression, hypermutation, smoking signature and mismatch repair (MMR) (HR, 0.30 [95% CI, 0.12-0.75], P = .010). Combined high TMB with APOBEC signature preferably predict immunotherapy responders in NSCLC cohort. The CIBERSORT algorithm revealed that high APOBEC mutational activity samples were associated with increased infiltration of CD4 memory activated T cells, CD8+ T cells and natural killer (NK) cells, but reduced infiltration of regulatory T cells. Besides, individual genes mutation of IFNGR1 or VTCN1 were only found in responders; however, the PTEN mutation was only found in non-responders (Fisher's exact test, all P < .05). These findings may be applicable for guiding immunotherapy for patients with NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Imunidade/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Mutação/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Feminino , Humanos , Imunidade/imunologia , Memória Imunológica/genética , Células Matadoras Naturais/imunologia , Masculino , Pessoa de Meia-Idade , Mutação/imunologia , Intervalo Livre de Progressão , Linfócitos T Reguladores/imunologia , Carga Tumoral/genética , Carga Tumoral/imunologia
13.
Vet Immunol Immunopathol ; 212: 38-42, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31213250

RESUMO

Food allergen-specific sublingual immunotherapy (FA-SLIT) is a novel, safe and effective approach in dogs with adverse food reactions (AFR) to reduce their clinical symptoms. However, little is known about the specific immune components which mediate this reduction in clinical symptoms. In humans, regulatory T cells seem to play an important role in this desensitisation process. Here, we investigated changes in peripheral T cell responses of dogs with AFR upon FA-SLIT. Five dogs received a dose escalation of FA-SLIT over a six-month period. An oral food challenge was performed at the beginning and end of the study to assess the efficacy of the FA-SLIT. Using in vitro allergen-recall assays, we assessed the proliferation of T cell subsets before and at the end of the treatment. FA-SLIT significantly increased the percentage of proliferating CD4-CD8- double-negative (DN) T cells, while the percentage of allergen-specific CD4-CD8+ and CD4+CD8+ double-positive (DP) T cells decreased upon treatment. These findings indicate that sublingual immunotherapy in dogs activates DN T cells, which might be important for the desensitisation of dogs with adverse food reactions. However, further research is needed to corroborate these findings and to further elucidate the mechanism of action of FA-SLIT in dogs with AFR.


Assuntos
Hipersensibilidade Alimentar/imunologia , Hipersensibilidade Alimentar/terapia , Imunoterapia Sublingual , Linfócitos T Reguladores/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Dessensibilização Imunológica/métodos , Cães , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Interleucina-10/imunologia , Ativação Linfocitária
14.
J Vet Sci ; 20(3): e28, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31161746

RESUMO

Buffalo mastitis is an important economic problem in southern Italy, causing qualitative/quantitative alterations in milk and resulting in economic losses due to the sub-clinical course and chronic evolution. We investigated 50 udders of slaughtered buffaloes and subjected them to effectual microbiological screening to evaluate macro and microscopic mammary gland changes, immune-characterize the cell infiltrates, and compare the degree of tissue inflammation with somatic cell counts. Numerous Gram-positive and Gram-negative bacteria were isolated from all samples, majority of which were environmental mastitis pathogens. Histological features referable to chronic mastitis were observed in 92% udders. Lymphocytes, plasma cells and macrophages were found to evolve into aggregates in 48% udders, which often organized to form tertiary lymphoid structures (TLSs). A predominance of interstitial CD8+ over CD4+ lymphocytes and, in TLSs, scattered CD8+ lymphocytes in the mantle cells and CD79+ lymphocytes in germinal centers, were evidenced. Environmental pathogens are known to persist and cause chronic inflammatory changes in buffaloes, where CD8+ lymphocytes play an important role by controlling the local immune response. Moreover, the TLSs evidenced here for the first time in buffalo mastitis, could play a role in maintaining immune responses against persistent antigens, thereby contributing in determining the chronic course of mastitis.


Assuntos
Fenômenos Fisiológicos Bacterianos/imunologia , Búfalos , Glândulas Mamárias Animais/microbiologia , Glândulas Mamárias Animais/patologia , Mastite/veterinária , Estruturas Linfoides Terciárias/veterinária , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Contagem de Células/veterinária , Doença Crônica/veterinária , Feminino , Glândulas Mamárias Animais/imunologia , Mastite/complicações , Mastite/microbiologia , Mastite/patologia , Estruturas Linfoides Terciárias/etiologia
15.
Nature ; 571(7763): 122-126, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31189952

RESUMO

Antibodies secreted into mucosal barriers serve to protect the host from a variety of pathogens, and are the basis for successful vaccines1. In type I mucosa (such as the intestinal tract), dimeric IgA secreted by local plasma cells is transported through polymeric immunoglobulin receptors2 and mediates robust protection against viruses3,4. However, owing to the paucity of polymeric immunoglobulin receptors and plasma cells, how and whether antibodies are delivered to the type II mucosa represented by the lumen of the lower female reproductive tract remains unclear. Here, using genital herpes infection in mice, we show that primary infection does not establish plasma cells in the lamina propria of the female reproductive tract. Instead, upon secondary challenge with herpes simplex virus 2, circulating memory B cells that enter the female reproductive tract serve as the source of rapid and robust antibody secretion into the lumen of this tract. CD4 tissue-resident memory T cells secrete interferon-γ, which induces expression of chemokines, including CXCL9 and CXCL10. Circulating memory B cells are recruited to the vaginal mucosa in a CXCR3-dependent manner, and secrete virus-specific IgG2b, IgG2c and IgA into the lumen. These results reveal that circulating memory B cells act as a rapidly inducible source of mucosal antibodies in the female reproductive tract.


Assuntos
Anticorpos/imunologia , Linfócitos B/citologia , Linfócitos B/imunologia , Movimento Celular/imunologia , Memória Imunológica/imunologia , Vagina/citologia , Vagina/imunologia , Animais , Formação de Anticorpos/imunologia , Linfócitos T CD4-Positivos/imunologia , Feminino , Herpes Simples/imunologia , Herpes Simples/virologia , Herpesvirus Humano 2/imunologia , Imunização , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Interferon gama/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Receptores CXCR3/imunologia , Vagina/virologia
16.
Cancer Sci ; 110(9): 2690-2699, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31250942

RESUMO

Senescence is a state of growth arrest induced not only in normal cells but also in cancer cells by aging or stress, which triggers DNA damage. Despite growth suppression, senescent cancer cells promote tumor formation and recurrence by producing cytokines and growth factors; this state is designated as the senescence-associated secretory phenotype. In this study, we examined the susceptibility of senescent human breast cancer cells to immune cell-mediated cytotoxicity. Doxorubicin (DXR) treatment induced senescence in 2 human breast cancer cell lines, MDA-MB-231 and BT-549, with the induction of γH2AX expression and increased expression of p21 or p16. Treatment with DXR also induced the expression of senescence-associated ß-galactosidase and promoted the production of pro-inflammatory cytokines. Importantly, DXR-treated senescent MDA-MB-231 cells showed increased sensitivity to 2 types of immune cell-mediated cytotoxicity: cytotoxicity of activated CD4+ T cells and Ab-dependent cellular cytotoxicity by natural killer cells. This increased sensitivity to cytotoxicity was partially dependent on tumor necrosis factor-related apoptosis-inducing ligand and perforin, respectively. This increased sensitivity was not observed following treatment with the senescence-inducing cyclin-dependent kinase-4/6 inhibitor, abemaciclib. In addition, treatment with DXR, but not abemaciclib, decreased the expression of antiapoptotic proteins in cancer cells. These results indicated that DXR and abemaciclib induced senescence in breast cancer cells, but that they differed in their sensitivity to immune cell-mediated cytotoxicity. These findings could provide an indication for combining anticancer immunotherapy with chemotherapeutic drugs or molecular targeting drugs.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/tratamento farmacológico , Linfócitos T CD4-Positivos/imunologia , Senescência Celular/imunologia , Células Matadoras Naturais/imunologia , Aminopiridinas/farmacologia , Aminopiridinas/uso terapêutico , Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Proteínas Reguladoras de Apoptose/imunologia , Proteínas Reguladoras de Apoptose/metabolismo , Benzimidazóis/farmacologia , Benzimidazóis/uso terapêutico , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linhagem Celular Tumoral , Senescência Celular/efeitos dos fármacos , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Terapia de Alvo Molecular/métodos , Recidiva Local de Neoplasia
17.
Nat Immunol ; 20(7): 824-834, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31209403

RESUMO

Multiple genome-wide studies have identified associations between outcome of human immunodeficiency virus (HIV) infection and polymorphisms in and around the gene encoding the HIV co-receptor CCR5, but the functional basis for the strongest of these associations, rs1015164A/G, is unknown. We found that rs1015164 marks variation in an activating transcription factor 1 binding site that controls expression of the antisense long noncoding RNA (lncRNA) CCR5AS. Knockdown or enhancement of CCR5AS expression resulted in a corresponding change in CCR5 expression on CD4+ T cells. CCR5AS interfered with interactions between the RNA-binding protein Raly and the CCR5 3' untranslated region, protecting CCR5 messenger RNA from Raly-mediated degradation. Reduction in CCR5 expression through inhibition of CCR5AS diminished infection of CD4+ T cells with CCR5-tropic HIV in vitro. These data represent a rare determination of the functional importance of a genome-wide disease association where expression of a lncRNA affects HIV infection and disease progression.


Assuntos
Regulação da Expressão Gênica , Variação Genética , Infecções por HIV/genética , Infecções por HIV/virologia , HIV-1 , RNA Antissenso/genética , RNA Longo não Codificante/genética , Receptores CCR5/genética , Regiões 3' não Traduzidas , Alelos , Biomarcadores , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/virologia , Membrana Celular/metabolismo , Genes Reporter , Genótipo , Infecções por HIV/metabolismo , Humanos , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único , Grupos Populacionais/genética , Prognóstico , Estabilidade de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores CCR5/metabolismo , Carga Viral
18.
Nat Commun ; 10(1): 2042, 2019 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-31053703

RESUMO

Metabolic pathways that regulate T-cell function show promise as therapeutic targets in diverse diseases. Here, we show that at rest cultured human effector memory and central memory CD4+ T-cells have elevated levels of glycolysis and oxidative phosphorylation (OXPHOS), in comparison to naïve T-cells. Despite having low resting metabolic rates, naive T-cells respond to TCR stimulation with robust and rapid increases in glycolysis and OXPHOS. This early metabolic switch requires Akt activity to support increased rates of glycolysis and STAT5 activity for amino acid biosynthesis and TCA cycle anaplerosis. Importantly, both STAT5 inhibition and disruption of TCA cycle anaplerosis are associated with reduced IL-2 production, demonstrating the functional importance of this early metabolic program. Our results define STAT5 as a key node in modulating the early metabolic program following activation in naive CD4+ T-cells and in turn provide greater understanding of how cellular metabolism shapes T-cell responses.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Fator de Transcrição STAT5/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Células Cultivadas , Ciclo do Ácido Cítrico/imunologia , Glicólise/imunologia , Voluntários Saudáveis , Humanos , Memória Imunológica , Ativação Linfocitária , Fosforilação Oxidativa , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-akt/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Fator de Transcrição STAT5/imunologia
19.
Pan Afr Med J ; 32: 2, 2019.
Artigo em Francês | MEDLINE | ID: mdl-31068996

RESUMO

Introduction: This study aimed to evaluate the performances of the MUSE® flow cytometer compared with the reference GUAVA® flow cytometer. Methods: We conducted an experimental study on HIV-infected patient samples. Venous blood samples, collected in a K3 EDTA tube, were analyzed within 24-48 hours by MUSE® and GUAVA® cytometers at the International Center for medical diagnosis (Centre International de Diagnostic médical) in Yaoundé. Results: In total, 227 samples were analyzed. There was a strong intraclass correlation (p<0.0001) between MUSE® and GUAVA® cytometers with a correlation coefficient 0.998 (95% CI: 0,998-0,999) for the absolute values and 0,992 (95% CI: 0,989-0,994) for the percentages. A strong positive linear correlation (p=0.0001) was found between MUSE® and GUAVA® cytometers with linear regression slope r2 = 0.98 (95% CI=0,97-0,99) for the absolute values and r2= 0.98 (95% CI= 0.96-1,00) for the percentages. The biases were -4,80 cells/µl (-101.31-91.71) for the absolute values and -0.89% (IC: -6,08-4.3) for the percentages. The percentage of data points outside the limits of agreement was 12/227 (5.29%) and 10/227 (4.41%) respectively for the absolute values and percentages. Cohen's kappa coefficient was 0.92 and the area under the curve was 0,9975 (CI 95%: 0.99-1). Conclusion: MUSE®AUTO CD4/CD4% cytometer is a powerful instrument because its results are consistent with those obtained by the reference cytometer. It can enable tracking of patients infected with HIV, in particular in the developing countries.


Assuntos
Contagem de Linfócito CD4/métodos , Linfócitos T CD4-Positivos/imunologia , Citometria de Fluxo/métodos , Infecções por HIV/diagnóstico , Adulto , Contagem de Linfócito CD4/instrumentação , Camarões , Feminino , Citometria de Fluxo/instrumentação , Infecções por HIV/imunologia , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade
20.
Nat Commun ; 10(1): 2296, 2019 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-31127086

RESUMO

Schistosoma mansoni (Sm) infection has been linked with an increased risk of HIV acquisition in women. Therefore, defining the mechanism(s) by which Sm alters HIV susceptibility might lead to new HIV prevention strategies. Here, we analyze the impact of standard Sm therapy in HIV-uninfected Sm+ Ugandan adult women on genital HIV susceptibility and mucosal and systemic immunology. Schistosomiasis treatment induces a profound reduction of HIV entry into cervical and blood CD4+ T cells that is sustained for up to two months, despite transient systemic and mucosal immune activation and elevated genital IL-1α levels. Genital IFN-α2a levels are also elevated post-treatment, and IFN-α2a blocks HIV entry into primary CD4+ T cells ex vivo. Transcriptomic analysis of blood mononuclear cells post-Sm treatment shows IFN-I pathway up-regulation and partial reversal of Sm-dysregulated interferon signaling. These findings indicate that Sm therapy may reduce HIV susceptibility for women with Sm infection, potentially through de-repression of IFN-I pathways.


Assuntos
Linfócitos T CD4-Positivos/parasitologia , HIV/efeitos dos fármacos , Esquistossomose mansoni/tratamento farmacológico , Esquistossomicidas/uso terapêutico , Internalização do Vírus/efeitos dos fármacos , Adulto , Animais , Linfócitos T CD4-Positivos/imunologia , Células Cultivadas , Colo do Útero/citologia , Colo do Útero/imunologia , Colo do Útero/patologia , Suscetibilidade a Doenças , Feminino , HIV/fisiologia , Infecções por HIV/imunologia , Infecções por HIV/prevenção & controle , Infecções por HIV/virologia , Humanos , Interferon-alfa/imunologia , Interferon-alfa/metabolismo , Praziquantel/farmacologia , Praziquantel/uso terapêutico , Cultura Primária de Células , Schistosoma mansoni/imunologia , Schistosoma mansoni/isolamento & purificação , Esquistossomose mansoni/sangue , Esquistossomose mansoni/imunologia , Esquistossomose mansoni/parasitologia , Esquistossomicidas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Uganda , Regulação para Cima , Esfregaço Vaginal , Adulto Jovem
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