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1.
Front Immunol ; 12: 623087, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34262557

RESUMO

Background: Seasonal variations have been reported for immune markers. However, the relative contributions of sunlight and vitamin D variability on such seasonal changes are unknown. Objective: This double-blind, randomized, placebo-controlled trial tested whether daily 400 IU vitamin D3 supplementation affected short-term (12 weeks) and long-term (43 weeks) natural regulatory T cell (nTreg) populations in healthy participants. Design: 62 subjects were randomized equally to vitamin D versus placebo in March and assessed at baseline, April (4w), June (12w), September (25w) and January (43w). Circulating nTregs, ex vivo proliferation, IL-10 and IFN-γ productions were measured. Vitamin D metabolites and sunlight exposure were also assessed. Results: Mean serum 25-hydroxyvitamin D (25(OH)D) increased from 35.8(SD 3.0) to 65.3(2.6) nmol/L in April and remained above 75 nmol/L with vitamin D supplementation, whereas it increased from 36.4(3.2) to 49.8(3.5) nmol/L in June to fall back to 39.6(3.5) nmol/L in January with placebo. Immune markers varied similarly between groups according to the season, but independently of 25(OH)D. For nTregs, the mean (%CD3+CD4+CD127lo cells (SEM)) nadir observed in March (2.9(0.1)%) peaked in September at 4.0(0.2)%. Mean T cell proliferation peaked in June (33156(1813) CPM) returning to the nadir in January (17965(978) CPM), while IL-10 peaked in June and reached its nadir in September (median (IQR) of 262(283) to (121(194) pg/ml, respectively). Vitamin D attenuated the seasonal increase in IFN-γ by ~28% with mean ng/ml (SEM) for placebo vs vitamin D, respectively, for April 12.5(1.4) vs 10.0(1.2) (p=0.02); June 13.9(1.3) vs 10.2(1.7) (p=0.02) and January 7.4(1.1) vs 6.0(1.1) (p=0.04). Conclusions: Daily low dose Vitamin D intake did not affect the nTregs population. There were seasonal variation in nTregs, proliferative response and cytokines, suggesting that environmental changes influence immune response, but the mechanism seems independent of vitamin D status. Vitamin D attenuated the seasonal change in T cell-produced IFN-γ, suggesting a decrease in effector response which could be associated with inflammation. Clinical Trial Registration: https://www.isrctn.com, identifier (ISRCTN 73114576).


Assuntos
Proliferação de Células/efeitos dos fármacos , Colecalciferol/administração & dosagem , Colecalciferol/imunologia , Interferon gama/análise , Estações do Ano , Linfócitos T Reguladores/imunologia , Adulto , Colecalciferol/sangue , Colecalciferol/farmacologia , Suplementos Nutricionais , Método Duplo-Cego , Feminino , Humanos , Inflamação/imunologia , Interferon gama/antagonistas & inibidores , Interferon gama/biossíntese , Interferon gama/imunologia , Interleucina-10/análise , Interleucina-10/imunologia , Masculino , Pessoa de Meia-Idade , Luz Solar , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/fisiologia
3.
FASEB J ; 35(8): e21754, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34191338

RESUMO

To obtain a successful pregnancy, the establishment of maternal-fetal tolerance and successful placentation are required to be established. Disruption of this immune balance and/or inadequate placental perfusion is believed to be associated with a lot of pregnancy-related complications, such as recurrent spontaneous abortion, pre-eclampsia, and fetal intrauterine growth restriction. Extravillous trophoblasts (EVTs) have the unique ability to instruct decidual immune cells (DICs) to develop a regulatory phenotype for fetal tolerance. Utilizing immortalized human first trimester extravillous trophoblast cells and primary EVTs, we found that DICs promote EVT function and placental development. We have previously shown that checkpoints T-cell immunoglobulin mucin-3 (Tim-3) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are important for DIC function. In the present study, we showed that blockade of Tim-3 and CTLA-4 pathways leaded to the abnormal DICs-EVTs interaction, poor placental development, and increased fetal loss. Treatment with IL-4 and IL-10 could rescue the adverse effects of targeting Tim-3 and CTLA-4 on the pregnancy outcome. Hence, the reproductive safety must be a criterion considered in the assessment of immuno-therapeutic agents. In addition, IL-4 and IL-10 may represent novel therapeutic strategies to prevent pregnancy loss induced by checkpoint inhibition.


Assuntos
Antígeno CTLA-4/imunologia , Decídua/imunologia , Receptor Celular 2 do Vírus da Hepatite A/imunologia , Interleucina-10/imunologia , Interleucina-4/imunologia , Trofoblastos/imunologia , Animais , Antígeno CTLA-4/antagonistas & inibidores , Comunicação Celular/imunologia , Células Cultivadas , Decídua/citologia , Perda do Embrião/imunologia , Feminino , Receptor Celular 2 do Vírus da Hepatite A/antagonistas & inibidores , Humanos , Tolerância Imunológica , Interleucina-10/administração & dosagem , Interleucina-4/administração & dosagem , Masculino , Troca Materno-Fetal/imunologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos CBA , Camundongos Endogâmicos DBA , Modelos Imunológicos , Placentação/imunologia , Gravidez , Resultado da Gravidez , Transdução de Sinais/imunologia , Trofoblastos/citologia
4.
Int J Mol Sci ; 22(11)2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-34073458

RESUMO

Cytotoxic CD4+ T cells (CD4 CTL) are terminally differentiated T helper cells that contribute to autoimmune diseases, such as multiple sclerosis. We developed a novel triple co-culture transwell assay to study mutual interactions between CD4 CTL, conventional TH cells, and regulatory T cells (Tregs) simultaneously. We show that, while CD4 CTL are resistant to suppression by Tregs in vitro, the conditioned medium of CD4 CTL accentuates the suppressive phenotype of Tregs by upregulating IL-10, Granzyme B, CTLA-4, and PD-1. We demonstrate that CD4 CTL conditioned medium skews memory TH cells to a TH17 phenotype, suggesting that the CD4 CTL induce bystander polarization. In our triple co-culture assay, the CD4 CTL secretome promotes the proliferation of TH cells, even in the presence of Tregs. However, when cell-cell contact is established between CD4 CTL and TH cells, the proliferation of TH cells is no longer increased and Treg-mediated suppression is restored. Taken together, our results suggest that when TH cells acquire cytotoxic properties, these Treg-resistant CD4 CTL affect the proliferation and phenotype of conventional TH cells in their vicinity. By creating such a pro-inflammatory microenvironment, CD4 CTL may favor their own persistence and expansion, and that of other potentially pathogenic TH cells, thereby contributing to pathogenic responses in autoimmune disorders.


Assuntos
Doenças Autoimunes/imunologia , Proliferação de Células , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Adulto , Antígeno CTLA-4/imunologia , Feminino , Granzimas/imunologia , Humanos , Interleucina-10/imunologia , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T Reguladores/citologia , Células Th17/citologia
5.
Front Immunol ; 12: 642860, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33995361

RESUMO

Cytokine storm (CS), an excessive release of proinflammatory cytokines upon overactivation of the innate immune system, came recently to the focus of interest because of its role in the life-threatening consequences of certain immune therapies and viral diseases, including CAR-T cell therapy and Covid-19. Because complement activation with subsequent anaphylatoxin release is in the core of innate immune stimulation, studying the relationship between complement activation and cytokine release in an in vitro CS model holds promise to better understand CS and identify new therapies against it. We used peripheral blood mononuclear cells (PBMCs) cultured in the presence of autologous serum to test the impact of complement activation and inhibition on cytokine release, testing the effects of liposomal amphotericin B (AmBisome), zymosan and bacterial lipopolysaccharide (LPS) as immune activators and heat inactivation of serum, EDTA and mini-factor H (mfH) as complement inhibitors. These activators induced significant rises of complement activation markers C3a, C4a, C5a, Ba, Bb, and sC5b-9 at 45 min of incubation, with or without ~5- to ~2,000-fold rises of IL-1α, IL-1ß, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13 and TNFα at 6 and 18 h later. Inhibition of complement activation by the mentioned three methods had differential inhibition, or even stimulation of certain cytokines, among which effects a limited suppressive effect of mfH on IL-6 secretion and significant stimulation of IL-10 implies anti-CS and anti-inflammatory impacts. These findings suggest the utility of the model for in vitro studies on CS, and the potential clinical use of mfH against CS.


Assuntos
COVID-19/imunologia , Ativação do Complemento , Síndrome da Liberação de Citocina/imunologia , Interleucina-10/imunologia , Interleucina-6/imunologia , Leucócitos Mononucleares/imunologia , Modelos Imunológicos , SARS-CoV-2/imunologia , COVID-19/patologia , Fator H do Complemento/imunologia , Síndrome da Liberação de Citocina/patologia , Humanos , Leucócitos Mononucleares/patologia , Leucócitos Mononucleares/virologia
6.
Mol Immunol ; 135: 36-44, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33857817

RESUMO

BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disease for which there are currently no effective therapies. Although mesenchymal stem cells (MSCs) can prevent arthritis through immunomodulatory mechanisms, there are several associated risks. Alternatively, MSC-derived small extracellular vesicles (sEVs) can mimic the effects of MSCs, while reducing the risk of adverse events. However, few studies have examined sEVs in the context of RA. Here, we evaluate the immunomodulatory effects of human umbilical cord MSC (hUCMSC)-derived sEVs on T lymphocytes in a collagen-induced arthritis (CIA) rat model to elucidate the possible mechanism of sEVs in RA treatment. We then compare these mechanisms to those of MSCs and methotrexate (MTX). METHODS: The arthritis index and synovial pathology were assessed. T lymphocyte proliferation and apoptosis, Th17 and Treg proportions, and interleukin (IL)-17, IL-10, and transforming growth factor (TGF)-ß expression were detected using flow cytometry. Retinoic acid receptor-related orphan receptor gamma t (RORγt) and forkhead box P3 (FOXP3), which are master transcriptional regulators of Th17 and Treg differentiation, were also assessed using immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: sEV treatment ameliorated arthritis and inhibited synovial hyperplasia in a dose-dependent manner. These effects were mediated by inhibiting T lymphocyte proliferation and promoting their apoptosis, while decreasing Th17 cell proportion and increasing that of Treg cells in the spleen, resulting in decreased serum IL-17, and enhanced IL-10 and TGF-ß expression. Transcriptionally, sEVs decreased RORγt and increased FOXP3 expression in the spleen, and decreased RORγt and FOXP3 expression in the joints. In some aspects sEVs were more effective than MSCs and MTX in treating CIA. CONCLUSIONS: hUCMSC-derived sEVs ameliorate CIA via immunomodulatory T lymphocytes, and might serve as a new therapy for RA.


Assuntos
Artrite Experimental/terapia , Vesículas Extracelulares/metabolismo , Imunomodulação/imunologia , Células-Tronco Mesenquimais/metabolismo , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Animais , Artrite Experimental/induzido quimicamente , Células Cultivadas , Colágeno/toxicidade , Modelos Animais de Doenças , Feminino , Fatores de Transcrição Forkhead/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Imunossupressores/farmacologia , Interleucina-10/imunologia , Interleucina-17/imunologia , Metotrexato/farmacologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Ratos , Ratos Wistar , Membrana Sinovial/patologia , Fator de Crescimento Transformador beta/metabolismo
7.
Int J Mol Sci ; 22(9)2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33925530

RESUMO

Regulatory B (Breg) cells are endowed with immune suppressive functions. Various human and murine Breg subtypes have been reported. While interleukin (IL)-10 intracellular staining remains the most reliable way to identify Breg cells, this technique hinders further essential functional studies. Recent findings suggest that CD9 is an effective surface marker of murine IL-10 competent Breg cells. However, the stability of CD9 and its relevance as a unique marker for human Breg cells, which have been widely characterized as CD24hiCD38hi, have not been investigated. Here, we demonstrate that CD9 expression is sensitive to in vitro B cell stimulations. CD9 expression could either be re-expressed or downregulated in purified CD9-negative B cells and CD9-positive B cells, respectively. We found no significant differences in the Breg differentiation capacity of the CD9-negative and CD9-positive B cells. Furthermore, CD9-positive B cells co-express CD40 and CD86, suggesting their nature as B cell activation or co-stimulatory molecules, rather than regulatory ones. Therefore, we report the relatively unstable CD9 as a distinct surface molecule, indicating the need for further research for a more reliable marker to purify human Breg cells.


Assuntos
ADP-Ribosil Ciclase 1/imunologia , Linfócitos B Reguladores/imunologia , Antígeno CD24/imunologia , Glicoproteínas de Membrana/imunologia , Tetraspanina 29/imunologia , Tecido Adiposo/citologia , Biomarcadores/análise , Diferenciação Celular/imunologia , Criança , Humanos , Interleucina-10/imunologia , Ativação Linfocitária , Células-Tronco Mesenquimais/imunologia , Tonsila Palatina/citologia , Regulação para Cima
8.
Int J Mol Sci ; 22(9)2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33925531

RESUMO

The impact of naturally occurring regulatory T cells (nTregs) on the suppression or induction of lung allergic responses in mice depends on the nuclear environment and the production of the pro-inflammatory cytokine interleukin 6 (IL-6). These activities were shown to be different in nTregs derived from wild-type (WT) and CD8-deficient mice (CD8-/-), with increased IL-6 levels in nTregs from CD8-/- mice in comparison to WT nTregs. Thus, identification of the molecular mechanisms regulating IL-6 production is critical to understanding the phenotypic plasticity of nTregs. Electrophoretic mobility shift assays (EMSA) were performed to determine transcription factor binding to four Il-6 promoter loci using nuclear extracts from nTregs of WT and CD8-/- mice. Increased transcription factor binding for each of the Il-6 loci was identified in CD8-/- compared to WT nTregs. The impact of transcription factor binding and a novel short tandem repeat (STR) on Il-6 promoter activity was analyzed by luciferase reporter assays. The Il-6 promoter regions closer to the transcription start site (TSS) were more relevant to the regulation of Il-6 depending on NF-κB, c-Fos, and SP and USF family members. Two Il-6 promoter loci were most critical for the inducibility by lipopolysaccharide (LPS) and tumor necrosis factor α (TNFα). A novel STR of variable length in the Il-6 promoter was identified with diverging prevalence in nTregs from WT or CD8-/- mice. The predominant GT repeat in CD8-/- nTregs revealed the highest luciferase activity. These novel regulatory mechanisms controlling the transcriptional regulation of the Il-6 promoter are proposed to contribute to nTregs plasticity and may be central to disease pathogenesis.


Assuntos
Hipersensibilidade/imunologia , Interleucina-6/imunologia , Pneumopatias/imunologia , Linfócitos T Reguladores/metabolismo , Adaptação Fisiológica/imunologia , Animais , Plasticidade Celular/genética , Plasticidade Celular/imunologia , Citocinas/imunologia , Interleucina-10/imunologia , Interleucina-6/genética , Pneumopatias/genética , Pneumopatias/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/imunologia , Regiões Promotoras Genéticas , Linfócitos T Reguladores/imunologia , Fator de Necrose Tumoral alfa/metabolismo
9.
PLoS One ; 16(3): e0247658, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33667240

RESUMO

Microsporidia are recognized as opportunistic pathogens in individuals with immunodeficiencies, especially related to T cells. Although the activity of CD8+ T lymphocytes is essential to eliminate these pathogens, earlier studies have shown significant participation of macrophages at the beginning of the infection. Macrophages and other innate immunity cells play a critical role in activating the acquired immunity. After programmed cell death, the cell fragments or apoptotic bodies are cleared by phagocytic cells, a phenomenon known as efferocytosis. This process has been recognized as a way of evading immunity by intracellular pathogens. The present study evaluated the impact of efferocytosis of apoptotic cells either infected or not on macrophages and subsequently challenged with Encephalitozoon cuniculi microsporidia. Macrophages were obtained from the bone marrow monocytes from C57BL mice, pre-incubated with apoptotic Jurkat cells (ACs), and were further challenged with E. cuniculi spores. The same procedures were performed using the previously infected Jurkat cells (IACs) and challenged with E. cuniculi spores before macrophage pre-incubation. The average number of spores internalized by macrophages in phagocytosis was counted. Macrophage expression of CD40, CD206, CD80, CD86, and MHCII, as well as the cytokines released in the culture supernatants, was measured by flow cytometry. The ultrastructural study was performed to analyze the multiplication types of pathogens. Macrophages pre-incubated with ACs and challenged with E. cuniculi showed a higher percentage of phagocytosis and an average number of internalized spores. Moreover, the presence of stages of multiplication of the pathogen inside the macrophages, particularly after efferocytosis of infected apoptotic bodies, was observed. In addition, pre-incubation with ACs or IACs and/or challenge with the pathogen decreased the viability of macrophages, reflected as high percentages of apoptosis. The marked expression of CD206 and the release of large amounts of IL-10 and IL-6 indicated the polarization of macrophages to an M2 profile, compatible with efferocytosis and favorable for pathogen development. We concluded that the pathogen favored efferocytosis and polarized the macrophages to an M2 profile, allowing the survival and multiplication of E. cuniculi inside the macrophages and explaining the possibility of macrophages acting as Trojan horses in microsporidiosis.


Assuntos
Apoptose/genética , Encephalitozoon cuniculi/imunologia , Evasão da Resposta Imune , Macrófagos/microbiologia , Esporos Fúngicos/imunologia , Animais , Medula Óssea/imunologia , Medula Óssea/microbiologia , Diferenciação Celular , Técnicas de Cocultura , Encephalitozoon cuniculi/genética , Encephalitozoon cuniculi/crescimento & desenvolvimento , Feminino , Expressão Gênica , Humanos , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Células Jurkat , Lectinas Tipo C/genética , Lectinas Tipo C/imunologia , Macrófagos/imunologia , Lectinas de Ligação a Manose/genética , Lectinas de Ligação a Manose/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Fagocitose , Cultura Primária de Células , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/imunologia , Esporos Fúngicos/genética , Esporos Fúngicos/crescimento & desenvolvimento
10.
Clin Exp Immunol ; 205(1): 75-88, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33759187

RESUMO

Follicular T helper (Tfh) and regulatory (Tfr) cells are distinct subsets of CD4+ T lymphocytes, regulating humoral immune responses in the germinal center. It is widely accepted that dysregulated Tfh and Tfr cells are associated with autoimmunity. In this study, we evaluated the frequencies of circulating chemokine receptor (CXCR)5+ programmed cell death 1 (PD-1+ ) Tfh (cTfh) and CXCR5+ PD-1+ forkhead box protein 3 (FoxP3+ ) CD25+ Tfr (cTfr) cells, and their corresponding cytokines from the peripheral blood mononuclear cells of 28 patients with relapsing-remitting multiple sclerosis (MS) and 16 age- and sex-matched healthy controls (HC). Subsets of cTfh cells by Th1- and Th17-related surface markers (CXCR3 and CCR6) were also evaluated. We found that the frequency of cTfh cells was significantly higher in MS patients compared to that of HC. Conversely, the frequency of cTfr cells was lower in MS patients than that of HC. Interleukin (IL)-21-producing cTfh cells were significantly increased in MS patients, while IL-10-secreting cTfr cells were lower in MS patients compared to levels in HC. Among cTfh cells, cTfh17.1 cells were the major subtypes that were significantly increased in MS patients compared to HC, with the frequency of IL-21-secreting cells being the highest. These results suggest that an imbalanced distribution of cTfh and cTfr exist in MS patients, which contributes to the reciprocally altered IL-21 and IL-10 production.


Assuntos
Citocinas/imunologia , Esclerose Múltipla Recidivante-Remitente/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Biomarcadores/metabolismo , Feminino , Fatores de Transcrição Forkhead/imunologia , Humanos , Interleucina-10/imunologia , Subunidade alfa de Receptor de Interleucina-2/imunologia , Interleucinas/imunologia , Leucócitos Mononucleares/imunologia , Masculino , Receptores CXCR5/imunologia , Células Th1/imunologia , Células Th17/imunologia
11.
Commun Biol ; 4(1): 342, 2021 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-33727664

RESUMO

Severe infection often causes a septic cytokine storm followed by immune exhaustion/paralysis. Not surprisingly, many pathogens are equipped with various anti-inflammatory mechanisms. Such mechanisms might be leveraged clinically to control septic cytokine storms. Here we show that N-glycan from pathogenic C. albicans ameliorates mouse sepsis through immunosuppressive cytokine IL-10. In a sepsis model using lipopolysaccharide (LPS), injection of the N-glycan upregulated serum IL-10, and suppressed pro-inflammatory IL-1ß, TNF-α and IFN-γ. The N-glycan also improved the survival of mice challenged by LPS. Analyses of structurally defined N-glycans from several yeast strains revealed that the mannose core is key to the upregulation of IL-10. Knocking out the C-type lectin Dectin-2 abrogated the N-glycan-mediated IL-10 augmentation. Furthermore, C. albicans N-glycan ameliorated immune exhaustion/immune paralysis after acute inflammation. Our results suggest a strategy where the immunosuppressive mechanism of one pathogen can be applied to attenuate a severe inflammation/cytokine storm caused by another pathogen.


Assuntos
Candida albicans/imunologia , Candidíase/imunologia , Parede Celular/imunologia , Citocinas/imunologia , Glicoproteínas de Membrana/imunologia , Polissacarídeos/imunologia , Sepse/imunologia , Animais , Candida albicans/metabolismo , Candidíase/metabolismo , Candidíase/microbiologia , Parede Celular/metabolismo , Células Cultivadas , Citocinas/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Interações Hospedeiro-Patógeno , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-10/imunologia , Interleucina-10/metabolismo , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Glicoproteínas de Membrana/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Polissacarídeos/metabolismo , Sepse/metabolismo , Sepse/microbiologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Fatores de Tempo , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo
12.
Life Sci ; 276: 119437, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33789145

RESUMO

In Coronavirus disease 2019 (COVID-19), a decreased number of regulatory T (Treg) cells and their mediated factors lead to a hyperinflammatory state due to overactivation of the inflammatory cells and factors during the infection. In the current study, we evaluated the Nanocurcumin effects on the Treg cell population and corresponding factors in mild and severe COVID-19 patients. To investigate the Nanocurcumin effects, 80 COVID-19 patients (40 at the severe stage and 40 at the mild stage) were selected and classified into Nanocurcumin and placebo arms. In both the Nanocurcumin and placebo groups, the Treg cell frequency, the gene expression of Treg transcription factor forkhead box P3 (FoxP3), and cytokines (IL-10, IL-35, and TGF-ß), as well as the serum levels of cytokines were measured before and after treatment. In both mild and severe COVID-19 patients, Nanocurcumin could considerably upregulate the frequency of Treg cells, the expression levels of FoxP3, IL-10, IL-35, and TGF-ß, as well as the serum secretion levels of cytokines in the Nanocurcumin-treated group compared to the placebo group. The abovementioned factors were remarkably increased in the post-treatment with Nanocurcumin before pre-treatment conditions. By contrast, it has been observed no notable alteration in the placebo group. Our findings revealed the SinaCurcumin® effective function in a significant increase in the number of Treg cells and their mediated factors in the Nanocurcumin group than in the placebo group in both mild and severe patients. Hence, it would be an efficient therapeutic agent in rehabilitating COVID-19 infected patients.


Assuntos
COVID-19/tratamento farmacológico , Curcumina/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Adulto , Idoso , COVID-19/imunologia , COVID-19/virologia , Citocinas/efeitos dos fármacos , Citocinas/imunologia , Feminino , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-10/imunologia , Interleucinas/imunologia , Masculino , Pessoa de Meia-Idade , Nanomedicina/métodos , RNA Viral/metabolismo , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/isolamento & purificação , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Fator de Crescimento Transformador beta/imunologia
13.
Int Immunopharmacol ; 94: 107475, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33662690

RESUMO

Interleukin (IL)-10 cytokine family members, including IL-10, IL-19, IL-20, IL-22, IL-24, IL-26 and the distantly related IL-28A, IL-28B, and IL-29, play critical roles in the regulation of inflammation. The occurrence and progression of cardiovascular diseases closely correlate with the regulation of inflammation, which may provide novel strategies for the treatment of cardiovascular diseases. In recent years, studies have focused on the association between the IL-10 cytokine family and the physiological and pathological progression of cardiovascular diseases. The aim of this review is to summarize relevant studies and clarify whether the IL-10 cytokine family contributes to the regulation of cardiovascular diseases.


Assuntos
Doenças Cardiovasculares/imunologia , Interleucina-10/imunologia , Animais , Humanos
14.
Nat Commun ; 12(1): 1893, 2021 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-33767202

RESUMO

B cells have essential functions in multiple sclerosis and in its mouse model, experimental autoimmune encephalomyelitis, both as drivers and suppressors of the disease. The suppressive effects are driven by a regulatory B cell (Breg) population that functions, primarily but not exclusively, via the production of IL-10. However, the mechanisms modulating IL-10-producing Breg abundance are poorly understood. Here we identify SLAMF5 for controlling IL-10+ Breg maintenance and function. In EAE, the deficiency of SLAMF5 in B cells causes accumulation of IL10+ Bregs in the central nervous system and periphery. Blocking SLAMF5 in vitro induces both human and mouse IL-10-producing Breg cells and increases their survival with a concomitant increase of a transcription factor, c-Maf. Finally, in vivo SLAMF5 blocking in EAE elevates IL-10+ Breg levels and ameliorates disease severity. Our results suggest that SLAMF5 is a negative moderator of IL-10+ Breg cells, and may serve as a therapeutic target in MS and other autoimmune diseases.


Assuntos
Linfócitos B Reguladores/imunologia , Encefalomielite Autoimune Experimental/patologia , Interleucina-10/imunologia , Família de Moléculas de Sinalização da Ativação Linfocitária/metabolismo , Animais , Sobrevivência Celular/imunologia , Células Cultivadas , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/imunologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Esclerose Múltipla/imunologia , Família de Moléculas de Sinalização da Ativação Linfocitária/antagonistas & inibidores , Família de Moléculas de Sinalização da Ativação Linfocitária/genética
15.
J Neuroimmunol ; 354: 577520, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33684831

RESUMO

Regulatory B cells are a rare B-cell subset widely known to exert their immunosuppressive function via the production of interleukin-10 (IL-10) and other mechanisms. B10 cells are a special subset of regulatory B cells with immunoregulatory function that is fully attributed to IL-10. Their unique roles in the animal model of multiple sclerosis (MS) have been described, as well as their relevance in MS patients. This review specifically focuses on the identification and development of B10 cells, the signals that promote IL-10 production in B cells, the roles of B10 cells in MS, and the potential and major challenges of the application of B10-based therapies for MS.


Assuntos
Linfócitos B Reguladores/imunologia , Interleucina-10/imunologia , Esclerose Múltipla/imunologia , Animais , Humanos , Imunoterapia/métodos
16.
Biomed Res Int ; 2021: 6633825, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33688497

RESUMO

Hypertension develops in the recipient rats that are transferred with the activated T helper (Th) 17 cells of the donor rats exposed to high-fructose or high-salt intake. This result suggests that a pathologic Th17 cell plays a role in the development and maintenance of hypertension. Here, we tested the hypothesis that the transfer of Th17 cells from adult spontaneous hypertensive rats (SHR) accelerates the development of hypertension in juvenile SHR. The tail-cuff method was used to measure systolic blood pressure. T cell (Th17 and regulatory T (Treg)) profiling was analyzed by flow cytometry. The expressions of Th17-related interleukin- (IL-) 17A and Treg-related IL-10 were measured by ELISA. Th17 cells isolated from adult SHR were intraperitoneally injected into juvenile recipient SHR and Wistar-Kyoto rats (WKY). SHR exhibited prominent development of hypertension at 15 weeks. The proportion of CD4+IL-17A+ (Th17) cells among Th cells increased whereas the proportion of CD4+FoxP3+ (Treg) cells decreased in SHR, as compared to WKY. The serum levels of IL-17A increased gradually with aging in SHR, but the serum levels of IL-10 did not. The serum levels of IL-17A and IL-10 seemed to be well related to the proportion of Th17 cells and Treg cells, respectively. Injection of Th17 cells isolated from adult SHR accelerates the development of hypertension in juvenile SHR but not in juvenile WKY though it increased the proportion of Th17 cells in juvenile recipient WKY and SHR. The transfer of Th17 cells from adult SHR accelerates the development of hypertension in juvenile SHR. These results implicate that the hypertension in SHR is ascribed to activation of Th17 cells.


Assuntos
Pressão Sanguínea/imunologia , Hipertensão , Transfusão de Linfócitos , Células Th17 , Animais , Modelos Animais de Doenças , Hipertensão/imunologia , Hipertensão/patologia , Hipertensão/fisiopatologia , Interleucina-10/imunologia , Interleucina-17/imunologia , Masculino , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia , Células Th17/imunologia , Células Th17/patologia , Células Th17/transplante
17.
Mol Immunol ; 133: 163-172, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33667986

RESUMO

Forkhead box P3 (Foxp3) expressing CD4+CD25+ regulatory T cells (Tregs), an essential subset of immune T cells for maintaining immune homeostasis is implicated as a negative regulator in an anti-tumor immune response. Current researches suggest that reducing tumor-infiltrating Tregs contribute to enhanced anti-cancer effect. However, the mechanism of infiltration of a large number of Tregs into tumor tissues is still unclear. In this study, human induced Tregs (iTregs) were co-cultured with human hepatocytes and various types of cancer cells (HepG2, NSCLC, and AsPC-1) supernatants. Foxp3, multiple cytokines, levels of apoptosis and suppressive ability of iTregs were detected by FACS. Western blot was employed to test of proteins. Impact of HepG2 supernatants on T cell subpopulations differentiation, cytokines in supernatants were examed by FACS and ELISA respectively. Anti-IL-10R antibody and JAK1 inhibitor were used to reconfirm the role of tumor-derived IL-10 play in the regulation on iTregs. Hepatocarcinoma cells (HCC) supernatants treatment increases Foxp3 stability and reduces apoptosis level in human iTregs without influencing its differentiation trend. Furthermore, IL-10 was found to be extremely higher in HCC supernatants than other groups, IL-10R blockade neutralize the effect of HCC supernatants on iTregs in vitro obviously. HCC supernatants also reversed IL-1ß/6 triggered decline on Foxp3 which may be related to higher expression of JAK1 and elevated phosphorylation level of STAT5 induced by IL-10. Our results suggest that improved stability and abnormal accumulation of Tregs in tumor microenvironment is IL-10/JAK1/STAT5 signal pathway-dependent and provide a novel approach for improving the efficiency of anti-tumor immunotherapy.


Assuntos
Interleucina-10/imunologia , Janus Quinase 1/metabolismo , Neoplasias Hepáticas/patologia , Fator de Transcrição STAT5/metabolismo , Linfócitos T Reguladores/imunologia , Microambiente Tumoral/imunologia , Proteínas Supressoras de Tumor/metabolismo , Adenocarcinoma/patologia , Adenoma/patologia , Apoptose/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Técnicas de Cocultura , Meios de Cultivo Condicionados/química , Fatores de Transcrição Forkhead/análise , Células Hep G2 , Hepatócitos/metabolismo , Humanos , Imunoterapia/métodos , Interleucina-10/análise , Janus Quinase 1/antagonistas & inibidores , Neoplasias Pulmonares/patologia , Neoplasias Pancreáticas/patologia , Receptores de Interleucina-10/antagonistas & inibidores
18.
J Int Med Res ; 49(3): 3000605211002695, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33745336

RESUMO

Over the past several decades, studies have demonstrated the existence of bi-directional relationships between periodontal disease and systemic conditions. Periodontitis is a polymicrobial and multifactorial disease involving both host and environmental factors. Tissue destruction is primarily associated with hyperresponsiveness of the host resulting in release of inflammatory mediators. Pro-inflammatory cytokines play a major role in bacterial stimulation and tissue destruction. In addition, these cytokines are thought to underlie the associations between periodontitis and systemic conditions. Current research suggests that increased release of cytokines from host cells, referred to as the cytokine storm, is associated with disease progression in patients with coronavirus disease 2019 (COVID-19). An intersection between periodontitis and pulmonary disease is biologically plausible. Hence, we reviewed the evidence linking COVID-19, cytokines, and periodontal disease. Plaque control is essential to prevent exchange of bacteria between the mouth and the lungs, reducing the risk of lung disease. Understanding these associations may help identify individuals at high risk and deliver appropriate care at early stages.


Assuntos
COVID-19/imunologia , Síndrome da Liberação de Citocina/imunologia , Placa Dentária/imunologia , Interações Hospedeiro-Patógeno/imunologia , Periodontite/imunologia , SARS-CoV-2/patogenicidade , Estresse Psicológico/imunologia , COVID-19/complicações , COVID-19/genética , COVID-19/virologia , Síndrome da Liberação de Citocina/complicações , Síndrome da Liberação de Citocina/genética , Síndrome da Liberação de Citocina/virologia , Placa Dentária/complicações , Placa Dentária/genética , Placa Dentária/virologia , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno/genética , Humanos , Interferon gama/genética , Interferon gama/imunologia , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Padrões Moleculares Associados a Patógenos/imunologia , Padrões Moleculares Associados a Patógenos/metabolismo , Periodontite/complicações , Periodontite/genética , Periodontite/virologia , SARS-CoV-2/imunologia , Transdução de Sinais , Estresse Psicológico/complicações , Estresse Psicológico/genética , Estresse Psicológico/virologia , Dente/imunologia , Dente/patologia , Dente/virologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
19.
Benef Microbes ; 12(1): 85-93, 2021 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-33550937

RESUMO

Several studies have demonstrated a decrease in upper respiratory infection (URI) frequency and severity in subjects taking probiotic supplements. We hypothesised beneficial effects of probiotics on viral URI in children are due to modulation of inflammatory innate immune responses. We tested this hypothesis, providing children with a probiotic combination of Lactobacillus acidophilus/Bidfidobacterium animalis ssp. lactis Bi-07 (NCFM/Bi-07) and measuring levels of cytokines in response to stimulation of peripheral blood mononuclear cells (PBMCs) to toll-like receptor (TLR) 7/8 agonist resiquimod (R848). In this open label study, 21 (2 dropouts) children received probiotic containing 5×109 cfu each of NCFM/(Bi-07) daily for 30 days. Whole blood was taken from each subject at study entry and 30 days for culture of PBMCs. PBMCs stimulated with resiquimod (R848) or unstimulated were incubated and a panel of immune markers was measured. There was a significant decrease in the net (stimulated-null) level of myeloid progenitor inhibitory factor 1 (MPIF-1) (mean decrease 0.1 ng/ml, 95% confidence interval 0.01-0.24, P=0.032) following probiotic supplementation. The change in immune marker levels after supplementation, when analysed together with respect to expected inflammatory/anti-inflammatory effects, was increased for interleukin (IL)-10 and decreased for MPIF-1, IL-8, interferon gamma induced protein 10, macrophage inflammatory protein 3 alpha (MIP-3α) and E-selectin (P=0.01). Adverse events were mild. In conclusion, supplementation with this probiotic combination was safe and resulted in significant modulation of PBMC limited immune response to TLR7/8 agonist R848 and in levels of MPIF-1 and MIP-3α. The anti-inflammatory effect may be one mechanism by which probiotics modulate the immune system however further study is needed.


Assuntos
Bifidobacterium animalis/fisiologia , Imidazóis/administração & dosagem , Lactobacillus acidophilus/fisiologia , Leucócitos Mononucleares/efeitos dos fármacos , Probióticos/administração & dosagem , Infecções Respiratórias/tratamento farmacológico , Pré-Escolar , Feminino , Humanos , Imunidade Inata , Lactente , Interleucina-10/genética , Interleucina-10/imunologia , Leucócitos Mononucleares/imunologia , Masculino , Infecções Respiratórias/genética , Infecções Respiratórias/imunologia , Receptor 7 Toll-Like/genética , Receptor 7 Toll-Like/imunologia , Receptor 8 Toll-Like/genética , Receptor 8 Toll-Like/imunologia
20.
Int J Mol Sci ; 22(3)2021 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-33572870

RESUMO

As a key anti-inflammatory cytokine, IL-10 is crucial in preventing inflammatory and autoimmune diseases. However, in human and murine lupus, its role remains controversial. Our aim was to understand regulation and immunologic effects of IL-10 on different immune functions in the setting of lupus. This was explored in lupus-prone NZB/W F1 mice in vitro and vivo to understand IL-10 effects on individual immune cells as well as in the complex in vivo setting. We found pleiotropic IL-10 expression that largely increased with progressing lupus, while IL-10 receptor (IL-10R) levels remained relatively stable. In vitro experiments revealed pro- and anti-inflammatory IL-10 effects. Particularly, IL-10 decreased pro-inflammatory cytokines and slowed B cell proliferation, thereby triggering plasma cell differentiation. The frequent co-expression of ICOS, IL-21 and cMAF suggests that IL-10-producing CD4 T cells are important B cell helpers in this context. In vitro and in vivo effects of IL-10 were not fully concordant. In vivo IL-10R blockade slightly accelerated clinical lupus manifestations and immune dysregulation. Altogether, our side-by-side in vitro and in vivo comparison of the influence of IL-10 on different aspects of immunity shows that IL-10 has dual effects. Our results further reveal that the overall outcome may depend on the interplay of different factors such as target cell, inflammatory and stimulatory microenvironment, disease model and state. A comprehensive understanding of such influences is important to exploit IL-10 as a therapeutic target.


Assuntos
Interleucina-10/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Imunidade Adaptativa , Animais , Autoimunidade , Linfócitos B/imunologia , Linfócitos B/metabolismo , Linfócitos B/patologia , Modelos Animais de Doenças , Progressão da Doença , Feminino , Expressão Gênica , Humanos , Imunidade Inata , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Interleucina-10/genética , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/patologia , Camundongos Endogâmicos NZB , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/patologia
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