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1.
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
2.
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
3.
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
4.
Cancer Immunol Immunother ; 68(7): 1211-1222, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31069460

RESUMO

Human tumor cells express antigens that serve as targets for the host cellular immune system. This phase 1 dose-escalating study was conducted to assess safety and tolerability of G305, a recombinant NY-ESO-1 protein vaccine mixed with glucopyranosyl lipid A (GLA), a synthetic TLR4 agonist adjuvant, in a stable emulsion (SE). Twelve patients with solid tumors expressing NY-ESO-1 were treated using a 3 + 3 design. The NY-ESO-1 dose was fixed at 250 µg, while GLA-SE was increased from 2 to 10 µg. Safety, immunogenicity, and clinical responses were assessed prior to, during, and at the end of therapy. G305 was safe and immunogenic at all doses. All related AEs were Grade 1 or 2, with injection site soreness as the most commonly reported event (100%). Overall, 75% of patients developed antibody response to NY-ESO-1, including six patients with increased antibody titer ( ≥ 4-fold rise) and three patients with seroconversion from negative (titer < 100) to positive (titer ≥ 100). CD4 T-cell responses were observed in 44.4% of patients; 33.3% were new responses and 1 was boosted ( ≥ 2-fold rise). Following treatment, 8 of 12 patients had stable disease for 3 months or more; at the end of 1 year, three patients had stable disease and nine patients were alive. G305 is a potent immunotherapeutic agent that can stimulate NY-ESO-1-specific antibody and T-cell responses. The vaccine was safe at all doses of GLA-SE (2-10 µg) and showed potential clinical benefit in this population of patients.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Antígenos de Neoplasias/administração & dosagem , Vacinas Anticâncer/administração & dosagem , Glucosídeos/administração & dosagem , Lipídeo A/administração & dosagem , Proteínas de Membrana/administração & dosagem , Neoplasias/terapia , Adjuvantes Imunológicos/efeitos adversos , Adulto , Idoso , Antígenos de Neoplasias/efeitos adversos , Antígenos de Neoplasias/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Vacinas Anticâncer/efeitos adversos , Vacinas Anticâncer/imunologia , Drogas em Investigação/administração & dosagem , Drogas em Investigação/efeitos adversos , Feminino , Glucosídeos/efeitos adversos , Glucosídeos/imunologia , Humanos , Imunogenicidade da Vacina , Injeções Intramusculares , Lipídeo A/efeitos adversos , Lipídeo A/imunologia , Masculino , Proteínas de Membrana/efeitos adversos , Proteínas de Membrana/imunologia , Pessoa de Meia-Idade , Neoplasias/imunologia , Neoplasias/patologia , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/imunologia , Receptor 4 Toll-Like/agonistas , Receptor 4 Toll-Like/imunologia , Resultado do Tratamento , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/efeitos adversos , Vacinas Sintéticas/imunologia , Adulto Jovem
5.
Cancer Immunol Immunother ; 68(7): 1095-1106, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31104075

RESUMO

Checkpoint blockade immunotherapy is now a first-line treatment option for patients with melanoma. Despite achieving objective responses in about half of patients, the exact immune mechanisms elicited and those required for therapeutic success have not been clearly identified. Insight into these mechanisms is key for improving outcomes in a broader range of cancer patients. We used a murine melanoma model to track responses by different subsets of tumor-infiltrating lymphocytes (TIL) during checkpoint blockade immunotherapy. Tumors from treated mice had increased frequencies of both CD4+ and CD8+ T cells, which also showed evidence of functional reinvigoration and elevated effector cytokine production after immunotherapy. We predicted that increased T cell numbers and function within tumors reflected either infiltration by new T cells or clonal expansion by a few high-affinity tumor-reactive T cells. To address this, we compared TIL diversity before and after immunotherapy by sequencing the complementarity determining region 3 (CDR3) of all T cell receptor beta (TCRß) genes. While checkpoint blockade effectively slowed tumor progression and increased T cell frequencies, the diversity of intratumoral T cells remained stable. This was true when analyzing total T cells and when focusing on smaller subsets of effector CD4+ and CD8+ TIL as well as regulatory T cells. Our study suggests that checkpoint blockade immunotherapy does not broaden the T cell repertoire within murine melanoma tumors, but rather expands existing T cell populations and enhances effector capabilities.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Melanoma Experimental/tratamento farmacológico , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Neoplasias Cutâneas/tratamento farmacológico , Animais , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Antígeno CTLA-4/antagonistas & inibidores , Linhagem Celular Tumoral , Regiões Determinantes de Complementaridade/genética , Humanos , Imunoterapia/métodos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Resultado do Tratamento , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
6.
Braz J Med Biol Res ; 52(5): e7992, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31038546

RESUMO

The aim of this study was to evaluate the influence of artesunate on Th1 differentiation and its anti-tumor effect on ovarian cancer. A Murine ovarian cancer model was established by ID8 cells transplantation. The expression of miR-142 and Sirt1 proteins in peripheral CD4+ T cells were quantified with qRT-PCR and western blot, respectively. Peripheral CD4+ T cells were induced for Th1 differentiation. The percentages of apoptosis of Th1/CD4+ T cells and ovarian cancer cells were analyzed by flow cytometry. The IFN-γ level was examined through enzyme-linked immunosorbent assay. Artesunate promoted miR-142 expression in peripheral CD4+ T cells and Th1 differentiation from CD4+ T cells. Artesunate promoted cell apoptosis of ovarian cancer cells by inducing Th1 differentiation. By up-regulating miR-142, artesunate suppressed Sirt1 level and promoted Th1 differentiation. Artesunate enhanced the pro-apoptotic effects of Th1 cells on ovarian cancer via the miR-142/Sirt1 pathway. Artesunate promoted Th1 differentiation from CD4+ T cells by down-regulating Sirt1 through miR-142, thereby enhancing cell apoptosis in ovarian cancer.


Assuntos
Apoptose , Artesunato/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , MicroRNAs/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Células Th1/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Artesunato/uso terapêutico , Linfócitos T CD4-Positivos/citologia , Diferenciação Celular , Regulação para Baixo , Feminino , Citometria de Fluxo , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Ovarianas/imunologia , Células Th1/citologia
7.
Cancer Immunol Immunother ; 68(7): 1059-1071, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30972427

RESUMO

Lung cancer is currently the leading cause of cancer-related mortality with very limited effective therapy. Screening of a variety of traditional Chinese medicines (TCMs) for their capacity to inhibit the proliferation of human lung cancer A549 cells and to induce the in vitro maturation of human DCs led to the identification of cryptotanshinone (CT), a compound purified from the TCM Salvia miltiorrhiza Bunge. Here, CT was shown to inhibit the proliferation of mouse Lewis lung carcinoma (LLC) cells by upregulating p53, downregulating cyclin B1 and Cdc2, and, consequently, inducing G2/M cell-cycle arrest of LLC cells. In addition, CT promoted maturation of mouse and human DCs with upregulation of costimulatory and MHC molecules and stimulated DCs to produce TNFα, IL-1ß, and IL-12p70, but not IL-10 in vitro. CT-induced maturation of DCs depended on MyD88 and also involved the activation of NF-κB, p38, and JNK. CT was effective in the treatment of LLC tumors and, when used in combination with low doses of anti-PD-L1, cured LLC-bearing mice with the induction of subsequent anti-LLC long-term specific immunity. CT treatment promoted T-cell infiltration and elevated the expression of genes typical of Th1 polarization in LLC tumor tissue. The therapeutic effect of CT and low doses of anti-PD-L1 was reduced by depletion of CD4 and CD8 T cells. This paper provides the first report that CT induces immunological antitumor activities and may provide a new promising antitumor immunotherapeutic.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Imunoterapia/métodos , Fenantrenos/farmacologia , Células A549 , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Carcinoma Pulmonar de Lewis/imunologia , Células Dendríticas/efeitos dos fármacos , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Fenantrenos/uso terapêutico , Resultado do Tratamento
8.
Ann Hematol ; 98(8): 1953-1959, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31025161

RESUMO

The change in the incidence of lymphomas in function of the presence or absence of sustained virological response after anti-hepatitis C therapy in a cohort of human immunodeficiency (HIV)-hepatitis C (HCV) viruses coinfected patients was analyzed. A prospective cohort of 755 HIV-HCV coinfected patients who received their first anti-HCV therapy, based on interferon + ribavirin schemas, was evaluated. Incidence and histologic types of lymphomas were analyzed in two periods: (1) before administration of anti-HCV therapy and (2) after anti-HCV therapy. The association between lymphoma incidence and demographic, HIV- (minimum CD4+ cell count and CD4+ cell count at diagnosis of lymphoma, antiretroviral therapy, maximal HIV load and HIV load at diagnosis of lymphoma) and HCV-related variables (HCV load, genotype, sustained viral response to anti-HCV therapy) were analyzed. A total of 13 lymphomas [incidence rate (95% confidence interval), 0.72 (0.33-1.11) × 1000 person-years, time from HIV diagnosis to lymphoma diagnosis (median, interquartile range), 15 (11-19) years] were diagnosed. Nine of them were non-Hodgkin and four Hodgkin lymphomas. The median CD4+ T cell count at diagnosis of lymphoma was 457/mm3, with only two cases with values lower than 200/mm3. The incidence rate of non-Hodgkin lymphomas was similar pre- and post-anti HCV therapy [0.33 (0.00-0.65) vs 0.68 (0.08-1.26) × 1000 person-years, respectively, p > 0.05]. Patients with sustained virologic HCV response showed similar incidence rate of lymphomas than that of those without anti-HCV response. In conclusion, anti-HCV therapy does not modify the incidence rate of lymphomas in HIV-HCV coinfected patients.


Assuntos
Antivirais/uso terapêutico , Infecções por HIV/tratamento farmacológico , Hepatite C Crônica/tratamento farmacológico , Doença de Hodgkin/tratamento farmacológico , Interferon alfa-2/uso terapêutico , Linfoma não Hodgkin/tratamento farmacológico , Ribavirina/uso terapêutico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Antirretroviral de Alta Atividade/métodos , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD4-Positivos/virologia , Coinfecção , Combinação de Medicamentos , HIV/efeitos dos fármacos , HIV/crescimento & desenvolvimento , Infecções por HIV/complicações , Infecções por HIV/patologia , Infecções por HIV/virologia , Hepacivirus/efeitos dos fármacos , Hepacivirus/crescimento & desenvolvimento , Hepatite C Crônica/complicações , Hepatite C Crônica/patologia , Hepatite C Crônica/virologia , Doença de Hodgkin/complicações , Doença de Hodgkin/patologia , Doença de Hodgkin/virologia , Humanos , Linfoma não Hodgkin/complicações , Linfoma não Hodgkin/patologia , Linfoma não Hodgkin/virologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Carga Viral/efeitos dos fármacos
9.
J Food Sci ; 84(4): 920-930, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30977922

RESUMO

Regulatory T cells (Tregs) control the reactivity of other T cells to prevent excessive inflammatory responses. They also plays a role in preventing autoimmune diseases; but when they are overproduced, they decreased vital immunity, which can lead to invasion of external pathogens. Therefore, it is most important in preventing the development of immune diseases to maintain the homeostasis of these cells. Delphinidin chloride is an anthocyanidin and known to have anti-oxidant activities. However, its structure is very unstable and easily decomposed. One of these degradation products is gallic acid, which also has anti-oxidant effects. In this study, we examined the effect of these materials on Tregs in controlling immune response. It was found that these materials further promote differentiation into Tregs, and TGF-ß and IL-2 related signals are involved in this process. Furthermore, it was verified that a variety of immunosuppressive proteins were secreted more, and the function of induced Tregs was also increased. Finally, in the allograft model, we could find a decrease in activated T cells when these materials were treated because they increased differentiation into Tregs. Therefore, these two materials are expected to become new candidates for the treatment of diseases caused by excessive activation of immune cells, such as autoimmune diseases. PRACTICAL APPLICATION: Delphinidin, a kind of anthocyanin rich in pigmented fruits, and its hydrolytic metabolite, gallic acid, are known to have antimicrobial and anti-oxidant properties. In this experiment, it was shown that delphinidin and gallic acid had an effect of increasing the differentiation of regulatory T cells, and the effect of suppressing the function of memory T cells was also observed. Due to these functions, delphinidin and gallic acid might have the potential to be used as immune suppressive agents in organ transplant and autoimmune disease patients or be a model for food development associated with the immune system.


Assuntos
Antocianinas/farmacologia , Ácido Gálico/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Aloenxertos , Animais , Antocianinas/química , Anti-Inflamatórios , Antioxidantes , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/fisiologia , Diferenciação Celular , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Cocultura , Ácido Gálico/química , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos , Neoplasias Experimentais , Linfócitos T Reguladores/metabolismo , Fator de Crescimento Transformador beta
10.
EBioMedicine ; 42: 97-108, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30824386

RESUMO

BACKGROUND: The latent HIV-1 reservoir in treated patients primarily consists of resting memory CD4+ T cells. Stimulating the T-cell receptor (TCR), which facilitates transition of resting into effector T cells, is the most effective strategy to purge these latently infected cells. Here we supply evidence that TCR-stimulated effector T cells still frequently harbor latent HIV-1. METHODS: Primary HIV-1 infected cells were used in a latency assay with or without dendritic cells (DCs) and reversion of HIV-1 latency was determined, in the presence or absence of specific pathway inhibitors. FINDINGS: Renewed TCR-stimulation or subsequent activation with latency reversing agents (LRAs) did not overcome latency. However, interaction of infected effector cells with DCs triggered further activation of latent HIV-1. When compared to TCR-stimulation only, CD4+ T cells from aviremic patients receiving TCR + DC-stimulation reversed latency more frequently. Such a "one-two punch" strategy seems ideal for purging the reservoir. We determined that DC contact activates the PI3K-Akt-mTOR pathway in CD4+ T cells. INTERPRETATION: This insight could facilitate the development of a novel class of potent LRAs that purge latent HIV beyond levels reached by T-cell activation.


Assuntos
Infecções por HIV/metabolismo , Infecções por HIV/virologia , HIV-1/fisiologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Latência Viral , Adulto , Idoso , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/virologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , HIV-1/efeitos dos fármacos , Humanos , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , NF-kappa B/metabolismo , Fosforilação , Ligação Proteica , Proteínas Proto-Oncogênicas c-fos/química , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteínas Proto-Oncogênicas c-jun/química , Proteínas Proto-Oncogênicas c-jun/metabolismo , Transdução de Sinais , Latência Viral/imunologia
11.
Proc Natl Acad Sci U S A ; 116(13): 6286-6291, 2019 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-30862736

RESUMO

Disruption of mucosal immunity plays a critical role in the pathogenesis of inflammatory bowel disease, yet its mechanism remains not fully elucidated. Here, we found that activating transcription factor 3 (ATF3) protects against colitis by regulating follicular helper T (TFH) cells in the gut. The expression of ATF3 in CD4+ T cells was negatively correlated with the severity of ulcerative colitis in clinical patients. Mice with ATF3 deficiency in CD4+ T cells (CD4 cre Atf3 fl/fl ) were much more susceptible to dextran sulfate sodium-induced colitis. The frequencies of TFH cells, not other T cell subsets, were dramatically decreased in Peyer's patches from CD4 cre Atf3 fl/fl mice compared with Atf3 fl/fl littermate controls. The defective TFH cells significantly diminished germinal center formation and IgA production in the gut. Importantly, adoptive transfer of TFH or IgA+ B cells caused significant remission of colitis in CD4 cre Atf3 fl/fl mice, indicating the TFH-IgA axis mediated the effect of ATF3 on gut homeostasis. Mechanistically, B cell lymphoma 6 was identified as a direct transcriptional target of ATF3 in CD4+ T cells. In summary, we demonstrated ATF3 as a regulator of TFH cells in the gut, which may represent a potential immunotherapeutic target in colitis.


Assuntos
Fator 3 Ativador da Transcrição/imunologia , Fator 3 Ativador da Transcrição/farmacologia , Colite/tratamento farmacológico , Colite/imunologia , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/imunologia , Fator 3 Ativador da Transcrição/genética , Fator 3 Ativador da Transcrição/metabolismo , Transferência Adotiva , Animais , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Colite/patologia , Colite Ulcerativa , Colo/patologia , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Homeostase , Imunidade nas Mucosas/imunologia , Imunoglobulina A , Imunoterapia , Camundongos , Nódulos Linfáticos Agregados/imunologia , Subpopulações de Linfócitos T
12.
Biomed Res Int ; 2019: 4650695, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30906773

RESUMO

Purpose: Oxaliplatin is a platinum-based chemotherapeutic agent demonstrating significant antitumor efficacy. Unlike conventional anticancer agents which are immunosuppressive, oxaliplatin has the capacity to stimulate immunological effects in response to the presentation of damage associated molecular patterns (DAMPs) elicited upon cell death. However, the effects of oxaliplatin treatment on systemic immune responses remain largely unknown. Aims of this study were to investigate the effects of oxaliplatin treatment on the proportions of (1) splenic T cells, B cells, macrophages, pro-/anti-inflammatory cytokines, gene expression of splenic cytokines, chemokines, and mediators; (2) double-positive and single-positive CD4+ and CD8+ T thymocytes; (3) bone-marrow hematopoietic stem and progenitor cells. Methods: Male BALB/c mice received intraperitoneal injections of oxaliplatin (3mg/kg/d) or sterile water tri-weekly for 2 weeks. Leukocyte populations within the spleen, thymus, and bone-marrow were assessed using flow cytometry. RT-PCR was performed to characterise changes in splenic inflammation-associated genes. Results: Oxaliplatin treatment reduced spleen size and cellularity (CD45+ cells), increased the proportion of CD4+, CD8+, and Treg cells, and elevated TNF-α expression. Oxaliplatin was selectively cytotoxic to B cells but had no effect on splenic macrophages. Oxaliplatin treatment altered the gene expression of several cytokines, chemokines, and cell mediators. Oxaliplatin did not deplete double-positive thymocytes but increased the single-positive CD8+ subset. There was also an increase in activated (CD69+) CD8+ T cells. Bone-marrow hematopoietic progenitor pool was demonstrably normal following oxaliplatin treatment when compared to the vehicle-treated cohort. Conclusion: Oxaliplatin does not cause systemic immunosuppression and, instead, has the capacity to induce beneficial antitumor immune responses.


Assuntos
Tolerância Imunológica/efeitos dos fármacos , Imunidade Celular/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Oxaliplatina/administração & dosagem , Animais , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/efeitos dos fármacos , Quimiocinas/genética , Quimiocinas/imunologia , Citocinas/genética , Citocinas/imunologia , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/imunologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/imunologia , Humanos , Imunidade Celular/imunologia , Masculino , Camundongos Endogâmicos BALB C , Neoplasias/imunologia , Oxaliplatina/imunologia , Baço/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Timócitos/efeitos dos fármacos , Timócitos/imunologia
13.
Molecules ; 24(6)2019 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-30893870

RESUMO

Cynatratoside A (CyA) is a C21 Steroidal glycoside with pregnane skeleton isolated from the root of Cynanchum atratum Bunge (Asclepiadaceae). This study aimed to investigate the effects of CyA on concanavalin A (Con A)-induced autoimmune hepatitis (AIH) and the underlying mechanism. CyA was orally administered to mice at 10 and 40 mg/kg 8 h before and 1 h after Con A treatment. The effects of CyA on Con A-induced spleen and liver in mice were assessed via histopathological changes, T lymphocyte amounts and the expressions of IL-1ß and ICAM-1. Con A-induced L-02 hepatocytes were used to evaluate whether CyA (0.1⁻10 µM) can directly protect hepatocytes from cytotoxicity and the possible mechanism. The results revealed that CyA treatment could significantly improve the histopathological changes of spleen and liver, reduce the proliferation of splenic T lymphocytes, and decrease the expressions of IL-1ß and ICAM-1 in liver. The experiment in vitro showed that CyA inhibited Con A-induced hepatotoxicity in a concentration-dependent manner. CyA (10 µM) significantly increased/decreased the expression of Bcl-2/Bax and reduced the levels of cleaved caspases-9 and -3. Our study demonstrated for the first time that CyA has a significant protective effect on Con A-induced AIH by inhibiting the activation and adhesion of T lymphocytes and blocking hepatocyte apoptosis.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/complicações , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Concanavalina A/toxicidade , Glicosídeos/química , Glicosídeos/uso terapêutico , Vincetoxicum/química , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Feminino , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Camundongos
14.
Carbohydr Polym ; 213: 370-381, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30879681

RESUMO

ß-glucans are polysaccharides comprising ß-D-glucoses with various bioactivities. Herein, we extracted three ß-glucans from Lentinus edodes with different sources and assessed their antitumor activities on a mice model with intragastric, intraperitoneal and intratumoral injection. Three polysaccharides were shown to have the same chemical structure of ß-(1,3)-glucan with ß-(1,6) branches, and exhibited S-180 tumor-suppressing ability with good safety. It was found that ß-glucans up-regulated CD4+ T cell level in lymphoid organs decreased by tumor-burden, indicating promotion of immunomodulation. ß-glucans targeted tumors in vivo even after oral or intraperitoneal injection. Furthermore, ß-glucans not only targeted to lymphoid organs and increased CD4+ T cells number, but also enhanced CD4+ T cells and neutrophils populations in tumors. It was proposed that ß-glucans promoted CD4+ T cell immunomodulation and neutrophils infiltration into tumors, leading to tumor growth inhibition. These findings reveal that ß-glucans can be used as an effective agent for cancer immunotherapy.


Assuntos
Antineoplásicos/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Imunomodulação/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , beta-Glucanas/farmacologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Imunomodulação/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Neutrófilos/imunologia , Imagem Óptica
15.
BMC Infect Dis ; 19(1): 207, 2019 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-30819101

RESUMO

BACKGROUND: The objective was to analyze the effectiveness and safety of dual therapy with rilpivirine plus boosted-darunavir (RPV + bDRV) in real-life patients. METHODS: Observational, retrospective, multi-center study in HIV+ patients who had received RPV + bDRV for 24 weeks to optimize/simplify their previous antiretroviral treatment. We determined the percentage of patients without virologic failure (2 consecutive viral loads > 50 copies/mL) at 24 weeks of treatment. RESULTS: The study included 161 patients from 15 hospitals with median age of 49 years; 29.3% had previous AIDS stage and median CD4+ lymphocyte nadir of 170 cells/uL. They had been diagnosed with HIV for a median of 17 years and had received 14 years of ART, with five previous treatment combinations, and 36.6% had a history of virological failure. The reasons for the switch were simplification/optimization (49.7%), toxicity/intolerance (17.4%), or inadequate effectiveness of previous ART (10.6%). Baseline VL of 50-1000 copies/mL was recorded in 25.5% of the patients. In the"intention-to-treat" analysis at 24 weeks, 87.6% of 161 patients continued the study treatment without virologic failure criteria. In the "on treatment" analysis (excluding patients who discontinued treatment with dual therapy for any reason other than virologic failure) the efficacy was 94.6% (141/149 patients). CONCLUSIONS: Dual therapy with RPV + DRVb proved to be effective and safe in patients with advanced HIV infection, long exposure to ART, low CD4 nadir, previous virologic failure, and/or history of ineffective ART.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Darunavir/uso terapêutico , Infecções por HIV/tratamento farmacológico , Rilpivirina/uso terapêutico , Adulto , Linfócitos T CD4-Positivos/efeitos dos fármacos , Quimioterapia Combinada , Feminino , Infecções por HIV/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Carga Viral
16.
Int J Biol Macromol ; 130: 229-237, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30797007

RESUMO

This study was designed to systematically elucidate the immunomodulation effect of glycosaminoglycan from Apostichopus japonicus (AHG) in cyclophosphamide (CY)-induced immunosuppression model and potential mechanism responsible for the activation of macrophages. The results showed that the treatment with AHG could increase natural killer (NK) cell cytotoxicity, carbon clearance and marker enzymes activities in CY-induced immunosuppression mice, indicating that the innate immunity experienced recovery to some extent. Moreover, CY-induced reductions in thymus and spleen indices, serum levels of cytokines, immunoglobulins and hemolysin, as well as the ratio of spleen lymphocyte subsets were recovered by AHG, suggesting that AHG could improve the adaptive immunity through cellular immunity and humoral immunity. Delightedly, it was found that AHG at 10 mg/kg body weight could restore the CY-induced immunosuppression in mice to normal level on both innate and adaptive immunity. Furthermore, AHG also promoted both the expression of NO, TNF-α, IL-6, IL-1ß, IL-18 and MCP-1 protein and related mRNA in macrophages. It was revealed that AHG activated macrophages through the phosphorylation of mitogen-activated protein kinase (MAPK) and nuclear factor-B (NF-κB). In conclusion, AHG exerts remarkable immunomodulatory activities in both innate and adaptive immune system. These findings should have great value for further study on the immunopotentiating mechanisms of this biomacromolecule.


Assuntos
Adjuvantes Imunológicos/farmacologia , Ciclofosfamida/farmacologia , Glicosaminoglicanos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Pepinos-do-Mar/química , Adjuvantes Imunológicos/química , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Glicosaminoglicanos/química , Proteínas Hemolisinas/sangue , Células Matadoras Naturais/imunologia , Ativação de Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Fagocitose/efeitos dos fármacos
17.
Nat Rev Clin Oncol ; 16(6): 356-371, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30705439

RESUMO

Regulatory T (Treg) cells, an immunosuppressive subset of CD4+ T cells characterized by the expression of the master transcription factor forkhead box protein P3 (FOXP3), are a component of the immune system with essential roles in maintaining self-tolerance. In addition, Treg cells can suppress anticancer immunity, thereby hindering protective immunosurveillance of neoplasia and hampering effective antitumour immune responses in tumour-bearing hosts, thus promoting tumour development and progression. Identification of the factors that are specifically expressed in Treg cells and/or that influence Treg cell homeostasis and function is important to understanding cancer pathogenesis and to identifying therapeutic targets. Immune-checkpoint inhibitors (ICIs) have provided a paradigm shift in the treatment of cancer. Most immune-checkpoint molecules are expressed in Treg cells, but the effects of ICIs on Treg cells, and thus the contributions of these cells to treatment responses, remain unclear. Notably, evidence indicates that ICIs targeting programmed cell death 1 (PD-1) might enhance the immunosuppressive function of Treg cells, whereas cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors might deplete these cells. Thus, although manipulation of Treg cells is a promising anticancer therapeutic strategy, approaches to controlling these cells require further research. Herein, we discuss novel insights into the roles of Treg cells in cancer, which can hopefully be used to develop Treg cell-targeted therapies and facilitate immune precision medicine.


Assuntos
Biomarcadores Tumorais/imunologia , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Fatores de Transcrição Forkhead/metabolismo , Homeostase , Humanos , Tolerância Imunológica , Imunoterapia , Medicina de Precisão , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Linfócitos T Reguladores/efeitos dos fármacos
18.
Biomed Pharmacother ; 112: 108580, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30784906

RESUMO

Obstructive sleep apnea (OSA) and high salt content in modern diet has been particularly implicated in systemic hypertension, leading to increased morbidity and mortality. Gut dysbiosis, associated with increased risk of systemic immunological imbalance, plays a causal role in the development of cardiovascular diseases. Here, we investigated the effect of Lactobacillus rhamnosus GG strain (LGG) on the development of hypertension induced by OSA and high salt diet. In this study, hypertension was modeled in rats by feeding a high salt diet (HSD) for 6 wk and exposuring to chronic intermittent hypoxia (CIH) during the sleep cycle. We found that OSA combined with HSD increased the severity of hypertension through increasing level of blood Trimethylamine-Oxide (TMAO), release of Th1-related cytokine (IFN-γ) and inhibition of anti-inflammatory cytokine (TGF-ß1), and affected the gut microbiome in rats, particularly by depleting Lactobacillus. In addition, expression of PERK1/2, PAkt and PmTOR increased in the aorta from rats with a CIH exposure and HSD. Consequently, treatment of model rats with LGG prevented aggravation of hypertension by reducing blood TMAO levels, modulating Th1/Th2 cytokine imbalance and suppressing phosphorylation levels of ERK1/2, Akt and mTOR. In line with these findings, our results connect high salt diet to the gut-immune axis and highlight the gut microbiome as a potential therapeutic target to counteract the development of OSA-induced hypertension basing on a high salt diet.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Hipertensão/metabolismo , Mediadores da Inflamação/metabolismo , Lactobacillus rhamnosus , Metilaminas/metabolismo , Apneia Obstrutiva do Sono/metabolismo , Cloreto de Sódio na Dieta/efeitos adversos , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Hipertensão/induzido quimicamente , Hipertensão/microbiologia , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/microbiologia , Masculino , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Apneia Obstrutiva do Sono/induzido quimicamente , Apneia Obstrutiva do Sono/microbiologia
19.
ACS Appl Mater Interfaces ; 11(10): 9824-9831, 2019 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-30758939

RESUMO

We describe the preparation and characterization of synthetic antibodies based on molecularly imprinted polymer nanoparticles (MIP-NPs) for the recognition and binding of the highly conserved and specific peptide motif SWSNKS (3S), an epitope of the envelope glycoprotein 41 (gp41) of human immunodeficiency virus type 1 (HIV-1). This motif is implicated in the decline of CD4+ T cells and leads to the deterioration of the immune system during HIV infection. Therefore, the development of MIP-NPs that can target and block the 3S peptide to prevent subsequent cascade interactions directed toward the killing of CD4+ T cells is of prime importance. Because most antibodies recognize their protein antigen via a conformational or structured epitope (as opposed to a linear epitope commonly used for molecular imprinting), we employed protein molecular modeling to design our template epitope so that it mimics the three-dimensional structure fold of 3S in gp41. The resulting template peptide corresponds to a cyclic structure composed of CGSWSNKSC, with the 3S motif well orientated for imprinting. MIP-NPs with a size of 65 nm were obtained by solid-phase synthesis and were water-soluble. They were prepared by a judicious combination of multiple functional monomers affording hydrogen bonding, ionic, π-π, and hydrophobic interactions, conferring high affinity and selectivity toward both the cyclic peptide and the whole gp41 protein. These results suggest that our MIPs could potentially be used for blocking the function of the 3S motif on the virus.


Assuntos
Anticorpos/administração & dosagem , Infecções por HIV/tratamento farmacológico , Impressão Molecular , Nanopartículas/administração & dosagem , Peptídeos/administração & dosagem , Motivos de Aminoácidos/imunologia , Anticorpos/imunologia , Formação de Anticorpos/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Epitopos/efeitos dos fármacos , Epitopos/imunologia , Proteína gp41 do Envelope de HIV/imunologia , Infecções por HIV/patologia , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/patogenicidade , Humanos , Ligações de Hidrogênio , Nanopartículas/química , Peptídeos/síntese química , Peptídeos/química , Polímeros/administração & dosagem , Polímeros/síntese química , Polímeros/química , Conformação Proteica/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Linfócitos T/virologia
20.
mSphere ; 4(1)2019 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-30760614

RESUMO

Type I interferons (IFNs) are key players in the antiviral immune response. Interferon alpha (IFN-α) belongs to this class of IFNs and comprises 12 subtypes that differ from each other in their binding affinities for a common receptor and, thus, in their signaling potencies. Recent data suggest that IFN-α6 and -α14 are the most potent IFN-α subtypes in restricting HIV replication when applied exogenously. However, in the context of antiviral therapy, IFNs are administered at high doses, which may compensate for differences in potency seen between IFN-α subtypes. In this study, we reexamined whether IFN-α subtypes induce different biological activities, with a focus on how IFN-α treatment dose affects cellular responses to HIV in primary CD4+ T cells, peripheral blood mononuclear cells (PBMCs), and macrophages. We found that the subtypes' antiviral activities were dose dependent, with >90% inhibition of HIV replication at a high dose of all IFN-αs except the weak IFN-α/ß receptor (IFNAR) binder, IFN-α1. The quality of the responses engendered by IFN-α1, -α2, -α6, and -α14 was highly comparable, with essentially the same set of genes induced by all four subtypes. Hierarchal cluster analysis revealed that the individual donors were stronger determinants for the IFN-stimulated-gene (ISG) responses than the specific IFN-α subtype used for stimulation. Notably, IFN-α2-derived mutants with substantially reduced IFNAR2 binding still inhibited HIV replication efficiently, whereas mutants with increased IFNAR1 binding potentiated antiviral activity. Overall, our results support the idea that IFN-α subtypes do not induce different biological responses, given that each subtype is exogenously applied at bioequivalent doses.IMPORTANCE Elucidating the functional role of the IFN-α subtypes is of particular importance for the development of efficacious therapies using exogenous IFN-α. Specifically, this will help define whether IFN therapy should be based on the use of pathogen-dependent IFN subtypes or, rather, IFN mutants with optimized IFNAR binding properties.


Assuntos
Antivirais/farmacologia , HIV/efeitos dos fármacos , Interferon-alfa/farmacologia , Replicação Viral/efeitos dos fármacos , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/virologia , Relação Dose-Resposta a Droga , Células HEK293 , Infecções por HIV/tratamento farmacológico , Humanos , Interferon-alfa/classificação , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/virologia , Macrófagos/efeitos dos fármacos , Macrófagos/virologia , Transdução de Sinais
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