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1.
Anticancer Res ; 40(1): 261-269, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892575

RESUMO

BACKGROUND: Pulmonary pleomorphic carcinoma (PPC) is a rare aggressive neoplasm, with dismal prognosis. Whether tumor immunity is associated with the progressive biological behavior of PPC remains unclear. The purpose of this study was to examine the prognostic significance of tumor immunity-related markers such as programmed death-1 ligand (PD-L1) and CD4+ or CD8+ tumor-infiltrating lymphocytes (TILs) in patients with surgically resected PPC. PATIENTS AND METHODS: Ninety-nine patients with surgically resected PPC were assessed by immunohistochemistry. The expression of PD-L1, CD4, and CD8 was examined in specimens of the resected tumors. RESULTS: PD-L1 was highly expressed in 61% (60/99) of lesions and high expression of CD4 and CD8 was identified in 42% (42/99) and 51% (51/99) of lesions, respectively. There was no relationship between the expression PD-L1 and the numbers of CD4+ or CD8+ TILs. The expression of PD-L1 was not identified as a significant prognostic marker; however, a low number of CD4+ TILs was identified as an independent marker for predicting a worse outcome after surgical resection of PPC, especially in patients with an epithelial component of adenocarcinoma or early stage of disease. By univariate analysis, a low number of CD8+ TILs was found to be a significant prognostic marker linked to poor overall survival in patients with non-adenocarcinoma components. CONCLUSION: A low number of CD4+ TILs is an independent marker for predicting a favorable prognosis after surgical resection in patients with PPC, especially in patients with adenocarcinoma components or early stage of disease.


Assuntos
Adenoma Pleomorfo/imunologia , Imunidade , Neoplasias Pulmonares/imunologia , Adenoma Pleomorfo/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/metabolismo , Antígenos CD4/metabolismo , Antígenos CD8/metabolismo , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico
2.
Int Arch Allergy Immunol ; 181(1): 71-80, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31722337

RESUMO

BACKGROUND: Few studies have directly compared the immunologic responses to specific subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT). OBJECTIVE: We aimed to directly compare clinical efficacy and immunological responses between SLIT and SCIT in allergic rhinitis (AR) sensitized to house dust mites. METHODS: Sixty-seven patients (age 5-55 years) with moderate-severe Dermatophagoides pteronyssinus (Der-p) and Dermatophagoides farinae AR with or without asthma were randomized (2:2:1) into SLIT (n = 27), SCIT (n = 26) and placebo (n = 14) groups. Symptom and medication scores, visual analogue score, serum Der-p specific immunoglobulin G4 (Der-p-sIgG4), CD4+CD25+FoxP3+ regulatory T cells (Tregs) and serum cytokines were measured. RESULTS: After 1-year treatment, a significant improvement of total rhinitis score (TRS), total rhinitis medication score (TRMS) and visual analogue score occurred in both SLIT and SCIT. There were no differences in clinical efficacy except for TRMS (p = 0.026) when SLIT and SCIT were directly compared. CD4+CD25+FoxP3+ Tregs had a trend towards upregulation in the 2 modes and inversely correlated with TRS (p = 0.024) only in SLIT. Der-p-sIgG4 significantly increased in SLIT and SCIT (p < 0.05), and it was 30 times higher in SCIT than SLIT after the treatment (p < 0.05). Serum interferon-γ significantly increased only in SCIT after 1 (p = 0.008), 6 (p = 0.007) and 12 (p = 0.008) months of treatment and inversely correlated with TRS (p = 0.032). CONCLUSION: While SCIT and SLIT have similar rates of clinical improvement, the 2 modes reveal heterogeneous changes of CD4+CD25+Foxp3+ Tregs, sIgG4 and cytokines.


Assuntos
Asma/terapia , Citocinas/sangue , Rinite Alérgica/terapia , Imunoterapia Sublingual/métodos , Linfócitos T Reguladores/imunologia , Adolescente , Adulto , Antígenos de Dermatophagoides/imunologia , Asma/complicações , Asma/imunologia , Antígenos CD4/metabolismo , Criança , Pré-Escolar , Estudos Controlados Antes e Depois , Feminino , Fatores de Transcrição Forkhead/metabolismo , Humanos , Infusões Subcutâneas , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Masculino , Pessoa de Meia-Idade , Rinite Alérgica/complicações , Rinite Alérgica/imunologia , Adulto Jovem
3.
Immunity ; 51(5): 915-929.e7, 2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31732167

RESUMO

The elicitation of broadly neutralizing antibodies (bNAbs) against the HIV-1 envelope glycoprotein (Env) trimer remains a major vaccine challenge. Most cross-conserved protein determinants are occluded by self-N-glycan shielding, limiting B cell recognition of the underlying polypeptide surface. The exceptions to the contiguous glycan shield include the conserved receptor CD4 binding site (CD4bs) and glycoprotein (gp)41 elements proximal to the furin cleavage site. Accordingly, we performed heterologous trimer-liposome prime:boosting in rabbits to drive B cells specific for cross-conserved sites. To preferentially expose the CD4bs to B cells, we eliminated proximal N-glycans while maintaining the native-like state of the cleavage-independent NFL trimers, followed by gradual N-glycan restoration coupled with heterologous boosting. This approach successfully elicited CD4bs-directed, cross-neutralizing Abs, including one targeting a unique glycan-protein epitope and a bNAb (87% breadth) directed to the gp120:gp41 interface, both resolved by high-resolution cryoelectron microscopy. This study provides proof-of-principle immunogenicity toward eliciting bNAbs by vaccination.


Assuntos
Vacinas contra a AIDS/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Anti-HIV/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Lipossomos , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Antígenos CD4/química , Antígenos CD4/imunologia , Antígenos CD4/metabolismo , Complemento C3/imunologia , Complemento C3/metabolismo , Apresentação Cruzada/imunologia , Epitopos/imunologia , Glicosilação , Infecções por HIV/virologia , Humanos , Imunoglobulina G/imunologia , Modelos Moleculares , Testes de Neutralização , Polissacarídeos/imunologia , Polissacarídeos/metabolismo , Ligação Proteica , Conformação Proteica , Coelhos , Produtos do Gene env do Vírus da Imunodeficiência Humana/administração & dosagem , Produtos do Gene env do Vírus da Imunodeficiência Humana/química , Produtos do Gene env do Vírus da Imunodeficiência Humana/metabolismo
4.
Medicine (Baltimore) ; 98(41): e17525, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31593126

RESUMO

To assess the intra-individual and inter-individuals biological variation and the effect of aging on lymphocyte T-cells subsets.We assessed lymphocyte phenotypes (CD3, CD4, and CD8 T-cells) in 89 HIV-1-infected and 88 uninfected white non-Hispanic men every 6 months, to examine the biological variation for those measurements, and the average change in lymphocyte phenotype over 34 years.The markers showed significant intra-individuality in HIV-infected and uninfected individuals with index of individuality of <1.4. No mean changes were seen over the 34 years, with the exception of percentage CD4T-cells in HIV-uninfected individuals.In the pre-HAART era, HIV-infected individuals experienced an increase in mean absolute CD3 T-cell numbers (11.21 cells/µL, P = 0.02) and absolute CD8 T-cell numbers (34.57 cell/µl, P < .001), and in the percentage of CD8 T-cells (1.45%, P < .001) per year and a significant decrease in mean absolute CD4 T-cell numbers (23.68 cells/µl, P < .001) and in the percentage of CD4 T-cells (1.49%, P < .001) per year.In the post-HAART era, no changes in mean levels were observed in absolute CD3 T-cell count (P = .15) or percentage (P = .99). Significant decreases were seen in mean count (8.56 cells/µl, P < .001) and percentage (0.59%, P < .001) of CD8 T-cells, and increases in mean absolute count (10.72 cells/µl, P < .001) and percentage (0.47%, P < .001) of CD4 T-cells.With the exception of CD4 (%), no average changes per year were seen in lymphocyte phenotype of HIV-uninfected men. The results of coefficients of variation of intra and inter-individuals of this study can be useful for HIV-1 infection monitoring and in addition the observation could be a useful guide for intra- and inter-individual coefficient variations, and establishing quality goal studies of different blood biomarkers in healthy and other diseases.


Assuntos
Síndrome de Imunodeficiência Adquirida/imunologia , Variação Biológica da População/imunologia , Infecções por HIV/imunologia , Subpopulações de Linfócitos T/imunologia , Síndrome de Imunodeficiência Adquirida/etnologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Terapia Antirretroviral de Alta Atividade/estatística & dados numéricos , Variação Biológica da População/etnologia , Biomarcadores/sangue , Complexo CD3/efeitos dos fármacos , Complexo CD3/imunologia , Complexo CD3/metabolismo , Antígenos CD4/imunologia , Antígenos CD4/metabolismo , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Senescência Celular/imunologia , Estudos de Coortes , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , Humanos , Los Angeles/epidemiologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Fenótipo , Subpopulações de Linfócitos T/metabolismo
5.
PLoS Pathog ; 15(9): e1008026, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31527908

RESUMO

The CD4 binding site (CD4bs) of the HIV-1 envelope glycoprotein is susceptible to multiple lineages of broadly neutralizing antibodies (bnAbs) that are attractive to elicit with vaccines. The CH235 lineage (VH1-46) of CD4bs bnAbs is particularly attractive because the most mature members neutralize 90% of circulating strains, do not possess long HCDR3 regions, and do not contain insertions and deletions that may be difficult to induce. We used virus neutralization to measure the interaction of CH235 unmutated common ancestor (CH235 UCA) with functional Env trimers on infectious virions to guide immunogen design for this bnAb lineage. Two Env mutations were identified, one in loop D (N279K) and another in V5 (G458Y), that acted synergistically to render autologous CH505 transmitted/founder virus susceptible to neutralization by CH235 UCA. Man5-enriched N-glycans provided additional synergy for neutralization. CH235 UCA bound with nanomolar affinity to corresponding soluble native-like Env trimers as candidate immunogens. A cryo-EM structure of CH235 UCA bound to Man5-enriched CH505.N279K.G458Y.SOSIP.664 revealed interactions of the antibody light chain complementarity determining region 3 (CDR L3) with the engineered Env loops D and V5. These results demonstrate that virus neutralization can directly inform vaccine design and suggest a germline targeting and reverse engineering strategy to initiate and mature the CH235 bnAb lineage.


Assuntos
Vacinas contra a AIDS/imunologia , /imunologia , Anticorpos Anti-HIV/biossíntese , Anticorpos Anti-HIV/imunologia , HIV-1/genética , HIV-1/imunologia , Produtos do Gene env do Vírus da Imunodeficiência Humana/genética , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia , Vacinas contra a AIDS/química , Vacinas contra a AIDS/genética , Substituição de Aminoácidos , Afinidade de Anticorpos , Sítios de Ligação , Antígenos CD4/metabolismo , Desenho de Drogas , Epitopos/química , Epitopos/genética , Epitopos/imunologia , Células HEK293 , Infecções por HIV/imunologia , Infecções por HIV/prevenção & controle , HIV-1/patogenicidade , Interações entre Hospedeiro e Microrganismos/genética , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Modelos Moleculares , Mutagênese Sítio-Dirigida , Engenharia de Proteínas , Multimerização Proteica , Estrutura Quaternária de Proteína , Produtos do Gene env do Vírus da Imunodeficiência Humana/química
6.
Cell Host Microbe ; 26(3): 359-368.e8, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31447307

RESUMO

Tetherin is a host defense factor that physically prevents virion release from the plasma membrane. The Nef accessory protein of simian immunodeficiency virus (SIV) engages the clathrin adaptor AP-2 to downregulate tetherin via its DIWK motif. As human tetherin lacks DIWK, antagonism of tetherin by Nef is a barrier to simian-human transmission of non-human primate lentiviruses. To determine the molecular basis for tetherin counteraction, we reconstituted the AP-2 complex with a simian tetherin and SIV Nef and determined its structure by cryoelectron microscopy (cryo-EM). Nef refolds the first α-helix of the ß2 subunit of AP-2 to a ß hairpin, creating a binding site for the DIWK sequence. The tetherin binding site in Nef is distinct from those of most other Nef substrates, including MHC class I, CD3, and CD4 but overlaps with the site for the restriction factor SERINC5. This structure explains the dependence of SIVs on tetherin DIWK and consequent barrier to human transmission.


Assuntos
Peptídeos Catiônicos Antimicrobianos/farmacologia , Antígeno 2 do Estroma da Médula Óssea/química , Antígeno 2 do Estroma da Médula Óssea/farmacologia , Infecções por Lentivirus/prevenção & controle , Infecções por Lentivirus/transmissão , Zoonoses/virologia , Complexo 2 de Proteínas Adaptadoras/química , Complexo 2 de Proteínas Adaptadoras/metabolismo , Subunidades beta do Complexo de Proteínas Adaptadoras/química , Animais , Sítios de Ligação , Complexo CD3/metabolismo , Antígenos CD4/metabolismo , Membrana Celular/efeitos dos fármacos , Microscopia Crioeletrônica , Regulação para Baixo , Produtos do Gene nef/química , Produtos do Gene nef/metabolismo , Células HEK293 , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Infecções por Lentivirus/virologia , Proteínas de Membrana/metabolismo , Modelos Moleculares , Cultura Primária de Células , Conformação Proteica , Conformação Proteica em alfa-Hélice , Dobramento de Proteína , Domínios e Motivos de Interação entre Proteínas , Alinhamento de Sequência , Síndrome de Imunodeficiência Adquirida dos Símios/prevenção & controle , Síndrome de Imunodeficiência Adquirida dos Símios/transmissão , Vírus da Imunodeficiência Símia/metabolismo , Vírion/efeitos dos fármacos
7.
Immunity ; 51(1): 141-154.e6, 2019 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-31315032

RESUMO

The VH1-2 restricted VRC01-class of antibodies targeting the HIV envelope CD4 binding site are a major focus of HIV vaccine strategies. However, a detailed analysis of VRC01-class antibody development has been limited by the rare nature of these responses during natural infection and the lack of longitudinal sampling of such responses. To inform vaccine strategies, we mapped the development of a VRC01-class antibody lineage (PCIN63) in the subtype C infected IAVI Protocol C neutralizer PC063. PCIN63 monoclonal antibodies had the hallmark VRC01-class features and demonstrated neutralization breadth similar to the prototype VRC01 antibody, but were 2- to 3-fold less mutated. Maturation occurred rapidly within ∼24 months of emergence of the lineage and somatic hypermutations accumulated at key contact residues. This longitudinal study of broadly neutralizing VRC01-class antibody lineage reveals early binding to the N276-glycan during affinity maturation, which may have implications for vaccine design.


Assuntos
Vacinas contra a AIDS/imunologia , Anticorpos Monoclonais/metabolismo , Anticorpos Neutralizantes/metabolismo , Anticorpos Anti-HIV/metabolismo , Infecções por HIV/imunologia , HIV-1/fisiologia , Vacinas contra a AIDS/genética , Sequência de Aminoácidos , Anticorpos Monoclonais/genética , Anticorpos Neutralizantes/genética , Afinidade de Anticorpos , Linfócitos B/imunologia , Antígenos CD4/metabolismo , Regiões Determinantes de Complementaridade/genética , Anticorpos Anti-HIV/genética , Proteína gp120 do Envelope de HIV/imunologia , Proteína gp120 do Envelope de HIV/metabolismo , Humanos , Polissacarídeos/metabolismo , Ligação Proteica
8.
Chin Med J (Engl) ; 132(10): 1188-1193, 2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-31140990

RESUMO

BACKGROUND: It is important to modulate the expression of glucocorticoids receptor (GR) in tress and maintain the immunity homeostasis in sepsis process. Rhubarb have been shown to have potential effects on anti-inflammatory and immune modulation. The present study was designed to investigate the effects of rhubarb on the expression of GR and cellular immunity in burn-induced septic rats. METHODS: Sixty-six healthy male Sprague Dawley (SD) rats were randomized into sepsis group (n = 24), rhubarb group (n = 24), and control group (n = 18); each group were further randomized into 12, 24, and 72 h subgroups according to different time points. During onset of the sepsis model, the rats in the rhubarb group were infused with 50 mg/kg rhubarb powder dissolved into 1 mL saline through gastric tube, while sepsis and control groups were treated with saline. The binding activity of GR in liver cytosol and binding capacity of GR in peripheral blood leucocyte were analyzed by radiation ligands binding assay. The percentages of CD4,CD8,CD4CD25T cells, CD19B cells as well as natural killer (NK) cells in the lymphocytes in peripheral blood were detected by flow cytometer. For assessing the differences among groups, one-way analysis of variance (ANOVA) with Scheffe multi-comparison techniques were employed. Comparisons between time-based measurements within each group were performed with ANOVA repeated measurement. RESULTS: The binding activity of GR in liver cytosol and binding capacity of GR in peripheral blood leucocyte were significantly decreased in a time-dependent manner in sepsis group (t = 23.045, P < 0.01; t = 24.395, P < 0.05, respectively), which were increased in a time-dependent manner after rhubarb administration (t = 19.965, P < 0.05; t = 17.140, P < 0.05, respectively). Twelve hours after sepsis, the percentages of CD4 T cells, CD4/CD25 T cell ratio, and CD19 B cells in the peripheral blood were significantly increased in the sepsis group (t = -3.395, P < 0.01; t = 2.568, P < 0.05; t = 2.993, P < 0.05, vs. control mice, respectively). However, the percentage of NK cells in the peripheral blood were significantly decreased in the sepsis group (t = -2.022, P < 0.05, vs. control mice). Twelve hours after sepsis, the percentage of CD8 T cells were significantly decreased in the peripheral blood in the sepsis group (t = -2.191, P < 0.05, vs. control mice) and were significantly increased in the rhubarb group (t = 2.953, P < 0.05, vs. sepsis mice). Seventy-two hours after sepsis, the ratio of CD4/CD25 T cell in peripheral blood were significantly increased in the sepsis group (t = 2.508, P < 0.05, vs. control mice) while were significantly decreased in the rhubarb group (t = 3.378, P < 0.05, vs. control mice). Furthermore, the percentages of CD19 B cell in peripheral blood were significantly decreased at 72 h in the rhubarb group (t = 2.041, P < 0.05 vs. sepsis group). CONCLUSIONS: Rhubarb might play potential anti-inflammatory and immunomodulatory roles in the sepsis processes.


Assuntos
Queimaduras/tratamento farmacológico , Queimaduras/metabolismo , Imunidade Celular/efeitos dos fármacos , Extratos Vegetais/uso terapêutico , Receptores de Glucocorticoides/metabolismo , Rheum/química , Sepse/tratamento farmacológico , Sepse/metabolismo , Análise de Variância , Animais , Anti-Inflamatórios/uso terapêutico , Linfócitos B/metabolismo , Queimaduras/imunologia , Antígenos CD4/metabolismo , Citometria de Fluxo , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Células Matadoras Naturais/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Sepse/imunologia , Linfócitos T/metabolismo , Linfócitos T Reguladores/metabolismo
9.
Genes Dev ; 33(11-12): 669-683, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30975723

RESUMO

The transcriptional repression of alternative lineage genes is critical for cell fate commitment. Mechanisms by which locus-specific gene silencing is initiated and heritably maintained during cell division are not clearly understood. To study the maintenance of silent gene states, we investigated how the Cd4 gene is stably repressed in CD8+ T cells. Through CRISPR and shRNA screening, we identified the histone chaperone CAF-1 as a critical component for Cd4 repression. We found that the large subunit of CAF-1, Chaf1a, requires the N-terminal KER domain to associate with the histone deacetylases HDAC1/2 and the histone demethylase LSD1, enzymes that also participate in Cd4 silencing. When CAF-1 was lacking, Cd4 derepression was markedly enhanced in the absence of the de novo DNA methyltransferase Dnmt3a but not the maintenance DNA methyltransferase Dnmt1. In contrast to Dnmt1, Dnmt3a deficiency did not significantly alter levels of DNA methylation at the Cd4 locus. Instead, Dnmt3a deficiency sensitized CD8+ T cells to Cd4 derepression mediated by compromised functions of histone-modifying factors, including the enzymes associated with CAF-1. Thus, we propose that the heritable silencing of the Cd4 gene in CD8+ T cells exploits cooperative functions among the DNA methyltransferases, CAF-1, and histone-modifying enzymes.


Assuntos
Antígenos CD4/genética , Fator 1 de Modelagem da Cromatina/metabolismo , DNA (Citosina-5-)-Metiltransferases/metabolismo , Proteína 4 de Ligação ao Retinoblastoma/metabolismo , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Animais , Antígenos CD4/metabolismo , DNA (Citosina-5-)-Metiltransferase 1/genética , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , DNA (Citosina-5-)-Metiltransferases/genética , Feminino , Regulação da Expressão Gênica , Inativação Gênica , Chaperonas de Histonas/metabolismo , Histona Desacetilases/metabolismo , Histonas/metabolismo , Masculino , Camundongos , Domínios Proteicos
10.
Nature ; 569(7754): 126-130, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30988509

RESUMO

The intestinal immune system has the challenging task of tolerating foreign nutrients and the commensal microbiome, while excluding or eliminating ingested pathogens. Failure of this balance leads to conditions such as inflammatory bowel diseases, food allergies and invasive gastrointestinal infections1. Multiple immune mechanisms are therefore in place to maintain tissue integrity, including balanced generation of effector T (TH) cells and FOXP3+ regulatory T (pTreg) cells, which mediate resistance to pathogens and regulate excessive immune activation, respectively1-4. The gut-draining lymph nodes (gLNs) are key sites for orchestrating adaptive immunity to luminal perturbations5-7. However, it is unclear how they simultaneously support tolerogenic and inflammatory reactions. Here we show that gLNs are immunologically specific to the functional gut segment that they drain. Stromal and dendritic cell gene signatures and polarization of T cells against the same luminal antigen differ between gLNs, with the proximal small intestine-draining gLNs preferentially giving rise to tolerogenic responses and the distal gLNs to pro-inflammatory T cell responses. This segregation permitted the targeting of distal gLNs for vaccination and the maintenance of duodenal pTreg cell induction during colonic infection. Conversely, the compartmentalized dichotomy was perturbed by surgical removal of select distal gLNs and duodenal infection, with effects on both lymphoid organ and tissue immune responses. Our findings reveal that the conflict between tolerogenic and inflammatory intestinal responses is in part resolved by discrete gLN drainage, and encourage antigen targeting to specific gut segments for therapeutic immune modulation.


Assuntos
Duodeno/imunologia , Linfonodos/imunologia , Linfócitos T/imunologia , Animais , Antígenos CD4/metabolismo , Diferenciação Celular , Movimento Celular , Polaridade Celular , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Duodeno/citologia , Duodeno/microbiologia , Feminino , Linfonodos/citologia , Linfonodos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Boca/imunologia , Boca/microbiologia , Ratos , Ratos Wistar , Células Estromais/imunologia , Células Estromais/microbiologia , Linfócitos T/citologia , Linfócitos T/microbiologia
11.
Cell Host Microbe ; 25(4): 578-587.e5, 2019 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-30974085

RESUMO

The HIV-1 envelope glycoprotein (Env) (gp120-gp41)3 is the target for neutralizing antibodies and antibody-dependent cellular cytotoxicity (ADCC). HIV-1 Env is flexible, sampling different conformational states. Before engaging CD4, Env adopts a closed conformation (State 1) that is largely antibody resistant. CD4 binding induces an intermediate state (State 2), followed by an open conformation (State 3) that is susceptible to engagement by antibodies that recognize otherwise occluded epitopes. We investigate conformational changes in Env that induce ADCC in the presence of a small-molecule CD4-mimetic compound (CD4mc). We uncover an asymmetric Env conformation (State 2A) recognized by antibodies targeting the conserved gp120 inner domain and mediating ADCC. Sera from HIV+ individuals contain these antibodies, which can stabilize Env State 2A in combination with CD4mc. Additionally, triggering State 2A on HIV-infected primary CD4+ T cells exposes epitopes that induce ADCC. Strategies that induce this Env conformation may represent approaches to fight HIV-1 infection.


Assuntos
Citotoxicidade Celular Dependente de Anticorpos , Linfócitos T CD4-Positivos/virologia , Anticorpos Anti-HIV/imunologia , HIV-1/imunologia , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia , Antígenos CD4/metabolismo , Células Cultivadas , Humanos , Ligação Proteica , Conformação Proteica , Produtos do Gene env do Vírus da Imunodeficiência Humana/química
12.
Dermatol Online J ; 25(2)2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30865410

RESUMO

A blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a cutaneous lymphoma derived from a plasmacytoid dendritic precursor cell that exhibits aggressive clinical behavior. Herein, we report a 46-year-old woman with a complaint of a painless nodule on the back, associated with pruritus. The nodule grew and new growths appeared over six months of evolution. The histopathological examination of one of the left upper limb lesions showed a dense lymphoid cell infiltrate with atypia in the superficial and deep dermis. Immunohistochemistry showed positivity for CD45, S-100 protein, CD123, and TCL 1. About two months after the initial evaluation, the patient was admitted to the Emergency Hospital of Marituba-PA with dyspnea. She progressed to cardiorespiratory arrest and death within 12 hours of admission. There is still no consensus for the treatment of BPDCN. Intensive therapy for acute leukemia can be useful, but allogeneic bone marrow transplantation has a greater chance of long-term survival.


Assuntos
Células Dendríticas/patologia , Linfoma/patologia , Neoplasias Cutâneas/patologia , Antígenos CD4/metabolismo , Evolução Fatal , Feminino , Humanos , Subunidade alfa de Receptor de Interleucina-3/metabolismo , Linfoma/metabolismo , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas/metabolismo , Proteínas S100/metabolismo , Neoplasias Cutâneas/metabolismo
13.
Mol Med Rep ; 19(5): 4081-4090, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30896871

RESUMO

The dendritic cell (DC)­regulatory T (Treg) system serves a leading role in the immunosuppression of the tumor microenvironment, which is not conducive to radiotherapy and chemotherapy treatment for lung cancer. The present study aimed to investigate the effect of oxymatrine (OMT) on the DC­Treg system in the tumor microenvironment in vitro and to examine its mechanism. The expressions of CD83 antigen, T­lymphocyte activation antigen CD86, CD11 antigen­like family member C and major histocompatibility complex II in DCs were increased upon treatment with 1 mg/ml OMT, as detected by flow cytometry. Following pretreatment with OMT, the DCs mediated the forkhead box protein P3 overexpression in primitive cluster of differentiation 4+ T cells at the protein and mRNA expression levels. The expression levels of anti­inflammatory factors, including interleukin (IL)­10, tumor growth factor­ß, IL­35, and pro­inflammatory cytokines, including interferon­Î³, IL­12 and IL­2, in the co­culture supernatant were increased as measured by ELISA. When DCs and DC­Tregs were co­cultured with cisplatin­resistant A549 cells, the proportion of apoptosis in the co­culture groups was increased under treatment with cisplatin, which was detected by Annexin V/propidium Iodide staining and western blotting. The present results suggested that OMT may promote the maturation of DCs, mediate the differentiation of T cells into Treg cells, and reverse the resistance of tumor cells to cisplatin in vitro. It was suggested that OMT is an important adjunct to chemotherapy through the regulation of antitumor responses.


Assuntos
Alcaloides/farmacologia , Células Dendríticas/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Quinolizinas/farmacologia , Linfócitos T Reguladores/imunologia , Células A549 , Adulto , Antígenos CD/metabolismo , Apoptose/efeitos dos fármacos , Antígenos CD4/metabolismo , Estudos de Casos e Controles , Células Cultivadas , Cisplatino/farmacologia , Citocinas/metabolismo , Células Dendríticas/citologia , Células Dendríticas/imunologia , Fatores de Transcrição Forkhead/metabolismo , Humanos , Imunoglobulinas/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/metabolismo
14.
Molecules ; 24(6)2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30897728

RESUMO

The objective of the present study was to compare the effects of the immunological activity of various parts (root/stem/leaf/flower/seed) of five-year-old ginseng on the immune system of immunosuppressive mice. Immunosuppression was induced by cyclophosphamide (CTX) in the mouse model, whereas levamisole hydrochloride tablet (LTH) was used for the positive control group. We found that ginseng root (GRT), ginseng leaf (GLF), and ginseng flower (GFR) could relieve immunosuppression by increased viability of NK cells, enhanced immune organ index, improved cell-mediated immune response, increased content of CD4⁺ and ratio of CD4⁺/CD8⁺, and recovery of macrophage function, including carbon clearance, phagocytic rate, and phagocytic index, in immunodeficient mice. However, ginseng stem (GSM) and ginseng seed (GSD) could only enhance the thymus indices, carbon clearance, splenocyte proliferation, NK cell activities, and the level of IL-4 in immunosuppressed mice. In CTX-injected mice, GRT and GFR remarkably increased the protein expression of Nrf2, HO-1, NQO1, SOD1, SOD2, and CAT in the spleen. As expected, oral administration of GRT and GFR markedly enhanced the production of cytokines, such as IL-1ß, IL-4, IL-6, IFN-γ, and TNF-α, compared with the CTX-induced immunosuppressed mice, and GRT and GFR did this relatively better than GSM, GLF, and GSD. This study provides a theoretical basis for further study on different parts of ginseng.


Assuntos
Ciclofosfamida/toxicidade , Imunossupressores/toxicidade , Panax/química , Extratos Vegetais/uso terapêutico , Animais , Peso Corporal/efeitos dos fármacos , Antígenos CD4/metabolismo , Antígenos CD8/metabolismo , Flores/química , Hospedeiro Imunocomprometido , Imunossupressão , Células Matadoras Naturais/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fagocitose/efeitos dos fármacos , Extratos Vegetais/química , Folhas de Planta/química , Ovinos
15.
Hum Immunol ; 80(7): 517-522, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30853363

RESUMO

INTRODUCTION: Chagas disease, caused by the protozoan Trypanosoma cruzi (T. cruzi), is the fourth most important tropical disease, which affects approximately 7 million people worldwide. The mechanisms involved in the development of this disease are not completely well understood. An important protective role of regulatory T cells (Treg) in Chagas disease has been observed; however, the specific mechanisms remain unclear. We evaluated apoptosis as a possible mechanism mediated by Treg cells (CD4+CD25HighFOXP3+) to orchestrate the immune response in chronic Chagas disease. METHODS AND RESULTS: Patients with Chagas disease were grouped as the indeterminate (IND; asymptomatic patients with Chagas disease; n = 10) and dilated cardiomyopathy (CARD; n = 10). Healthy T. cruzi-negative individuals (NI; n = 10) were included as a control group. In order to evaluate the apoptotic cell profile, the expression of PD1, PD1L, CD39, CD95, CD95L molecules were investigated. We also evaluated the proportion of CD14+ cells expressing caspase 3. The IND group presented a substantially higher expression of CD39 by Treg cells as compared to the CARD group. On the other hand, the CARD group showed higher expression of PD-1 by Treg cells than both NI and IND groups. Significant positive correlations were observed between Treg CD95L+ cells and CD14 cells expressing caspase 3 as well as between Treg CD39 cells and CD14+ Caspase3+ cells in the IND group. CONCLUSION: Our data indicate that the expressions of different molecules that induce apoptosis are associated with suppressive mechanisms mediated by Treg cells and suggest a possible role for PD1 and PDL1 molecules in the morbidity of chronic Chagas disease.


Assuntos
Antígeno B7-H1/metabolismo , Cardiomiopatia Dilatada/sangue , Cardiomiopatia Chagásica/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T Reguladores/imunologia , Trypanosoma cruzi/imunologia , Adulto , Idoso , Antígenos de Protozoários/imunologia , Apoptose/imunologia , Apirase/metabolismo , Antígenos CD4/metabolismo , Feminino , Fatores de Transcrição Forkhead/metabolismo , Humanos , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Masculino , Pessoa de Meia-Idade , Testes Sorológicos
16.
Int Immunopharmacol ; 70: 313-323, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30852287

RESUMO

Immunoglobulin A nephropathy (IgAN) is an autoimmune kidney disease with complex pathogenesis leading to end-stage renal damage. The crucial pathological characteristic in IgAN is IgA immune complexes deposition accompany with mesangial cell proliferation and mesangial matrix expansion. Artemisinin (ART) is isolated from traditional Chinese medicine Artemisia annua L. Hydroxychloroquine (HCQ) is a classical antimalarial drug used to treat autoimmune diseases. Both of them possess immunosuppressive, immunomodulatory and anti-inflammatory features. The aim of this study was to investigate the pharmacological effects of ART combined with HCQ (AH) and explore the underlying mechanisms in IgAN. In vivo, our results showed that AH could significantly improve kidney dysfunction, decrease mesangial matrix expansion as well as immune complexes in mesangial area visualized by H&E and PAS staining. The depositions of IgA immune complexes and complement 3 (C3) were obviously reduced after AH treatment by immunofluorescence. Interestingly, the morphology of kidney and spleen was significantly swelled but reverted by AH in IgAN rats. Further mechanistic study showed that the higher proportions of the Th2 and Th17 cells were reduced but the lower differentiation of Th1 and Treg cells subsets were promoted by AH. Taken together, this study demonstrated that there was an immunosuppressive effect of AH therapy on IgAN rats via regulating the differentiation of CD4+ T cell subsets, which provided an alternative approach for IgAN treatment.


Assuntos
Artemisininas/uso terapêutico , Quimioterapia Combinada , Glomerulonefrite por IGA/tratamento farmacológico , Hidroxicloroquina/uso terapêutico , Imunossupressores/uso terapêutico , Células Mesangiais/fisiologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Células Th2/imunologia , Animais , Complexo Antígeno-Anticorpo/metabolismo , Artemisia annua/imunologia , Antígenos CD4/metabolismo , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Humanos , Masculino , Medicina Tradicional Chinesa , Ratos , Ratos Sprague-Dawley
17.
Int Immunopharmacol ; 69: 194-201, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30735938

RESUMO

CD4+ regulatory T cells (Tregs) play an important role in inducing immune tolerance in organ transplantation, which can be divided into CD45RA+Tregs (resting Tregs, rTregs) and CD45RO+Tregs (activated Tregs, aTregs). Currently, the expressions and phenotypic changes of Tregs in recipients after liver transplantation (LT) is unknown. We therefore investigated the expression and transformation of rTregs and aTregs in 83 cases of recipients with normal status post-LT. The percentages of CD45RA, CD45RO, CD31 in CD4+Tregs were detected by flow cytometry and the effective factors were analyzed. In LT recipients, the percentage of CD45RO+Tregs in CD4+Tregs was higher than that of CD45RA+Tregs. There was significant difference in the ratio of positive Foxp3 between CD45RA+Tregs and CD45RO+Tregs. Percentage of CD45RA+Tregs was higher in pediatric group than that in adult group, whereas percentage of CD45RO+Tregs was lower in the pediatric group. However, it was different only in CD45RO+Tregs in various survival periods post-LT. In conclusion, Tregs pool in human was heterogeneous post-LT and contained different subsets in phenotypes. Upon stimulation by donor graft, percentages of CD4+Tregs and CD45RO+Tregs were increased post-LT and most of rTregs was transformed into aTregs in peripheral blood, and rTregs and aTregs were both related to recipients' ages.


Assuntos
Rejeição de Enxerto/imunologia , Transplante de Fígado , Linfócitos T Reguladores/imunologia , Adulto , Fatores Etários , Antígenos CD4/metabolismo , Separação Celular , Células Cultivadas , Criança , Pré-Escolar , Feminino , Citometria de Fluxo , Fatores de Transcrição Forkhead/metabolismo , Antígenos HLA/imunologia , Humanos , Tolerância Imunológica , Imunofenotipagem , Lactente , Isoantígenos/imunologia , Antígenos Comuns de Leucócito/metabolismo , Masculino , Pessoa de Meia-Idade , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Transplantados
18.
Mol Cell Neurosci ; 95: 71-78, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30738184

RESUMO

Interleukin 16 (IL-16) is a cytokine that is primarily associated with CD4+ T cell function, but also exists as a multi-domain PDZ protein expressed within cerebellar and hippocampal neurons. We have previously shown that lymphocyte-derived IL-16 is neuroprotective against excitotoxicity, but evidence of how it affects neuronal function is limited. Here, we have investigated whether IL-16 modulates neuronal excitability and synaptic activity in mouse primary hippocampal cultures. Application of recombinant IL-16 impairs both glutamate-induced increases in intracellular Ca2+ and sEPSC frequency and amplitude in a CD4- and CD9-independent manner. We examined the mechanisms underlying these effects, with rIL-16 reducing GluA1 S831 phosphorylation and inhibiting Na+ channel function. Taken together, these data suggest that IL-16 reduces neuronal excitability and synaptic activity via multiple mechanisms and adds further evidence that alternative receptors may exist for IL-16.


Assuntos
Potenciais Pós-Sinápticos Excitadores , Interleucina-16/farmacologia , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Receptores de AMPA/metabolismo , Canais de Sódio/metabolismo , Animais , Antígenos CD4/metabolismo , Cálcio/metabolismo , Células Cultivadas , Ácido Glutâmico/toxicidade , Hipocampo/citologia , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Neurônios/fisiologia , Fosforilação , Tetraspanina 29/metabolismo
19.
J Virol ; 93(8)2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30728264

RESUMO

Lactobacillus bacteria are potential delivery vehicles for biopharmaceutical molecules because they are well-recognized as safe microorganisms that naturally inhabit the human body. The goal of this study was to employ these lactobacilli to combat human immunodeficiency virus type 1 (HIV-1) infection and transmission. By using a chromosomal integration method, we engineered Lactobacillus acidophilus ATCC 4356 to display human CD4, the HIV-1 receptor, on the cell surface. Since human CD4 can bind to any infectious HIV-1 particles, the engineered lactobacilli can potentially capture HIV-1 of different subtypes and prevent infection. Our data demonstrate that the CD4-carrying bacteria are able to adsorb HIV-1 particles and reduce infection significantly in vitro and also block intrarectal HIV-1 infection in a humanized mouse model in preliminary tests in vivo Our results support the potential of this approach to decrease the efficiency of HIV-1 sexual transmission.IMPORTANCE In the absence of an effective vaccine, alternative approaches to block HIV-1 infection and transmission with commensal bacteria expressing antiviral proteins are being considered. This report provides a proof-of-concept by using Lactobacillus bacteria stably expressing the HIV-1 receptor CD4 to capture and neutralize HIV-1 in vitro and in a humanized mouse model. The stable expression of antiviral proteins, such as CD4, following genomic integration of the corresponding genes into this Lactobacillus strain may contribute to the prevention of HIV-1 sexual transmission.


Assuntos
Antígenos CD4/metabolismo , Infecções por HIV/prevenção & controle , HIV-1/metabolismo , Lactobacillus acidophilus/metabolismo , Animais , Antígenos CD4/genética , Linhagem Celular , Feminino , Infecções por HIV/genética , Infecções por HIV/metabolismo , HIV-1/genética , Humanos , Lactobacillus acidophilus/genética , Masculino , Camundongos , Camundongos Knockout , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo
20.
Allergol. immunopatol ; 47(1): 43-46, ene.-feb. 2019. graf, tab
Artigo em Inglês | IBECS | ID: ibc-180770

RESUMO

Background: It is considered that farm areas protect young patients from allergy and asthma due to high exposure to endotoxins. Aim: To compare CD4+/CD25+ T-regulatory cells and forkhead transcription factor Foxp3 expression in asthmatic children allergic to house dust mites (HDM) living in rural and farm areas. Materials and Methods: This was a prospective analysis of 35 children living in farm areas (n = 19) and rural areas (n = 16), aged 8-16, with allergic rhinitis (allergic to dust mites) and newly diagnosed asthma. Surface molecule CD4+CD25+Foxp3+ expression on cultured PBMCs was estimated by flow cytometry using fluorophore-conjugated monoclonal antibodies in each patient. Results: Thirty-five children were included into the analysis: 19 children living in farm areas and 16 in rural areas. Within and between-groups (farm area vs. rural area) differences in CD4+/CD25+ and CD4+/CD25+Foxp3+ cell expression did not reach the level of significance. Conclusion: The current analysis showed that CD4+/CD25+ and CD4+/CD25+Foxp3+ cell expression was not associated with place of living in asthmatic children sensitive to HDM


No disponible


Assuntos
Humanos , Animais , Masculino , Feminino , Criança , Adolescente , Asma/imunologia , Rinite Alérgica/imunologia , População Rural , Linfócitos T Reguladores/imunologia , Antígenos de Dermatophagoides/imunologia , Asma/epidemiologia , Antígenos CD4/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Polônia/epidemiologia , Estudos Prospectivos , Pyroglyphidae/imunologia , Rinite Alérgica/epidemiologia
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