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1.
Xenotransplantation ; 26(4): e12522, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31077480

RESUMO

Monitoring for immune rejection is crucial for long-term survival of pig xenografts. Circulating DNA is a promising non-invasive biomarker for either organ injury or response to therapy. In this study, circulating pig-specific DNA (cpsDNA) was monitored during xenograft rejection. Potential targets of cpsDNA were selected by in silico analysis, and species specificity of selected primers was confirmed by PCR. Subsequently, cpsDNA as a biomarker was evaluated using a complement-dependent cytotoxicity (CDC) assay in vitro. Then, early diagnosis and response to rapamycin were assessed by an in vivo imaging model of pig-to-mouse cell transplantation. Finally, cpsDNA was monitored in a pig-to-monkey artery patch transplantation model. The results showed that (a) a method of cpsDNA quantitation was established for application in mouse and nonhuman primate models; (b) cpsDNA reflected CDC in vitro; (c) cpsDNA in vivo mirrored xenograft rejection, and correlated with xenograft loss in pig-to-mouse cell transplantation; (d) cpsDNA was significantly reduced when rapamycin was administered; and (e) dynamic cpsDNA was detectable in pig-to-monkey artery patch transplantation. In conclusion, measurement of cpsDNA could prove to be a less invasive, but more specific and sensitive low-cost biomarker enabling monitoring of xenograft rejection and the response to immunosuppressive therapy.

2.
J Leukoc Biol ; 106(3): 733-747, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30861206

RESUMO

Host-pathogen interactions in tuberculosis (TB) should be studied at the disease sites because Mycobacterium tuberculosis (M.tb) is predominantly contained in local tissue lesions. T-cell immune responses are required to mount anti-mycobacterial immunity. However, T-cell immune responses modulated by programmed cell death protein 1 (PD-1) during tuberculosis pleurisy (TBP) remains poorly understood. We selected the pleural fluid mononuclear cells (PFMCs) from TBP and PBMCs from healthy donors (HD), and characterized PD-1-expresing T-cell phenotypes and functions. Here, we found that the PFMCs exhibited increases in numbers of PD-1-expressing CD4+ and CD8+ T cells, which preferentially displayed polarized effector memory phenotypes. The M.tb-specific Ag stimulation increased CD4+ PD-1+ and CD8+ PD-1+ T cells, which is in direct correlation with IFN-γ production and PD-L1+ APCs in PFMCs of these individuals. Moreover, blockage of PD-1/PD-L1 pathway enhanced the percentage of IFN-γ+ T cells, demonstrating that the PD-1/PD-L1 pathway played a negative regulation in T cell effector functions. Furthermore, CD4+ PD-1+ and CD8+ PD-1+ T-cell subsets showed greater memory phenotype, activation, and effector functions for producing Th1 cytokines than PD-1- counterparts. Thus, these PD-1+ T cells were not exhausted but appear to be central to maintaining Ag-specific effector. IL-12, a key immunoregulatory cytokine, enhanced the expression of PD-1 and restored a strong IFN-γ response through selectively inducing the phosphorylation of STAT4 in CD4+ PD-1+ T-bet+ and CD8+ PD-1+ T-bet+ T cells. This study therefore uncovered a previously unknown mechanism for T-cell immune responses regulated by PD-1, and may have implications for potential immune intervention in TBP.

3.
J Cell Mol Med ; 2018 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-30353641

RESUMO

Sustained adaptive immunity to pathogens provides effective protection against infections, and effector cells located at the site of infection ensure rapid response to the challenge. Both are essential for the success of vaccine development. To explore new vaccination approach against Mycobacterium tuberculosis (M.tb) infection, we have shown that Rv3615c, identified as ESX-1 substrate protein C of M.tb but not expressed in BCG, induced a dominant Th1-type response of CD4+ T cells from patients with tuberculosis pleurisy, which suggests a potential candidate for vaccine development. But subcutaneous immunization with Rv3615c induced modest T-cell responses systemically, and showed suboptimal protection against virulent M.tb challenge at the site of infection. Here, we use a mouse model to demonstrate that intranasal immunization with Rv3615c induces sustained capability of adaptive CD4+ T- and B-cell responses in lung parenchyma and airway. Rv3615c contains a dominant epitope of mouse CD4+ T cells, Rv3615c41-50 , and elicits CD4+ T-cell response with an effector-memory phenotype and multi-Th1-type cytokine coexpressions. Since T cells resident at mucosal tissue are potent at control of infection at early stage, our data show that intranasal immunization with Rv3615c promotes a sustained regional immunity to M.tb, and suggests a potency in control of M.tb infection. Our study warranties a further investigation of Rv3615c as a candidate for development of effective vaccination against M.tb infection.

4.
Front Immunol ; 9: 2287, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30344522

RESUMO

Recent studies indicated that CXCR5+CD8+ T cells in lymph nodes could eradicate virus-infected target cells. However, in the current study we found that a subset of CXCR5+CD8+ T cells in the germinal centers from human tonsils or lymph nodes are predominately memory cells that express CD45RO and CD27. The involvement of CXCR5+CD8+ T cells in humoral immune responses is suggested by their localization in B cell follicles and by the concomitant expression of costimulatory molecules, including CD40L and ICOS after activation. In addition, CXCR5+CD8+ memory T cells produced significantly higher levels of IL-21, IFN-γ, and IL-4 at mRNA and protein levels compared to CXCR5-CD8+ memory T cells, but IL-21-expressing CXCR5+CD8+ T cells did not express Granzyme B and perforin. When cocultured with sorted B cells, sorted CXCR5+CD8+ T cells promoted the production of antibodies compared to sorted CXCR5-CD8+ T cells. However, fixed CD8+ T cells failed to help B cells and the neutralyzing antibodies against IL-21 or CD40L inhibited the promoting effects of sorted CXCR5+CD8+ T cells on B cells for the production of antibodies. Finally, we found that in the germinal centers of lymph nodes from HIV-infected patients contained more CXCR5+CD8+ T cells compared to normal lymph nodes. Due to their versatile functional capacities, CXCR5+CD8+ T cells are promising candidate cells for immune therapies, particularly when CD4+ T cell help are limited.

5.
Med Sci Monit ; 24: 4952-4960, 2018 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-30011399

RESUMO

The aim of this study was to report aseptic, erosive polyarthritis in a patient with common variable immunodeficiency (CVID), which is quite different from the vastly more common nonerosive form. Peripheral blood mononuclear cells of the patient were isolated. Flow cytometry was used to analyze the proportion and function of lymphocytes. A Parker-Pearson needle biopsy was performed on the right knee. Four of her unaffected family members were enrolled as controls. A 21-year-old woman was admitted for recurrent polyarthritis of 3-year duration. The right knee, hip, wrist, proximal interphalangeal joints, and left elbow were involved, with progressive joint destruction. She was diagnosed as having CVID based on her recurrent infections, poor response to vaccines, and marked hypogammaglobulinemia. No bacterium or mycobacterium was detected in synovium or synovial fluid. The synovium was infiltrated by lymphocytes rather than neutrophils. Polyarthritis did not resolve by adequate intravenous immunoglobulin substitution and empirical antibiotic treatment, but resolved gradually after treatment with methylprednisolone and tacrolimus, supporting the diagnosis of aseptic polyarthritis. Further analyses showed that although only 0.5% of residual B lymphocytes were existent in peripheral blood of the patient, expressions of activation marker CD69 and production of IL-1ß, IL-6, and TNF-α were high. Marked infiltration with CD19+B lymphocytes (as well as CD4+ or CD8+ T lymphocytes) was detected in the synovium. The proportion of IL21+CD4+Th cells from peripheral blood of the patient was high. CD4+ Th cells from the patient secreted nearly 3 times more IL-21 than the same cell type analyzed from unaffected family members, perhaps due to excessive compensation to assist the function of residual B lymphocytes. A novel hypothesis in CVID concurrent with aseptic, erosive polyarthritis is that excessive activation of residual B lymphocytes infiltrate into the synovium of the involved joints and lead to polyarthritis and joint destruction.


Assuntos
Artrite/metabolismo , Artrite/fisiopatologia , Linfócitos B/imunologia , Adulto , Linfócitos B/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , China , Imunodeficiência de Variável Comum/complicações , Citocinas/metabolismo , Feminino , Citometria de Fluxo , Humanos , Interleucina-2/metabolismo , Leucócitos Mononucleares/metabolismo , Ativação Linfocitária/imunologia , Masculino , Adulto Jovem
6.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 34(4): 289-295, 2018 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-29973317

RESUMO

Objective To investigate the recovery effects of IL-12 on the immune suppression induced by chemotherapeutic medicine in patients and mouse with malignant tumors. Methods Peripheral blood mononuclear cells (PBMCs) from tumor patients with or without chemotherapy and healthy donors were stimulated with or without anti-CD3 antibody plus anti-CD28 antibody in the presence or absent of IL-12. The levels of IFN-γ and TNF-α in culture supernatants were detected by enzyme-linked immunosorbent assay (ELISA). The expression of IFN-γ in different subsets of T cells was analyzed by fluorescence activated cell sorter (FACS). Finally, we established the cisplatin toxicity mouse model and measured the levels of IFN-γ and TNF-α by ELISA and FACS. Results PBMCs from the patients with malignant tumors produced significantly lower levels of IFN-γ and TNF-α than PBMCs from healthy donors. The production of IFN-γ and TNF-α was higher in pre-chemotherapeutic patients compared with post-chemotherapeutic patients, whereas IL-12 could remarkably recover the production of IFN-γ and TNF-α in the patients with malignant tumors. FACS showed that IL-12 recovered the expression of IFN-γ by CD4+ and CD8+ T cells in post-chemotherapeutic patients. Finally, the results from the animal studies in vitro and in vivo proved that IL-12 recovered the inhibitory effect of chemotherapeutic drugs on immune function. Conclusion Chemotherapeutics inhibits the immune responses in patients and animals, and IL-12 can recover the suppressive effects of chemotherapeutics on the production of cytokines. Our results indicated that IL-12 might play an important role in the reconstruction of immune function in cancer patients with chemotherapeutics.

7.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 33(11): 1448-1455, 2017 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-29268845

RESUMO

Objective To study the inhibitory effect of tofacitinib on the production of cytokines by T cells in human peripheral blood and its mechanism. Methods Peripheral blood mononuclear cells (PBMCs) and purified T cells were cultured and stimulated with anti-CD3 plus anti-CD28 antibodies in the presence or absence of tofacitinib (0.5 µmol/L). The levels of interferon γ (IFN-γ), tumor necrosis factor α (TNF-α) and interleukin 2 (IL-2) in the culture supernatants were detected by ELISA, and the expressions of activated molecules CD69 and CD25 on the surface of CD4+ and CD8+ T cells, the production of cytokines and the phosphorylation of signal transducers and transcriptional activators STAT1, STAT3, STAT4 in T cells were examined by flow cytometry. At the same time, the proliferation and apoptosis of T cells were observed by 5- (and 6-) carboxyfluorescein diacetate succinimidyl ester (CFSE) staining and the flow cy tometry with annexin V-FITC/PI, respectively. Results Tofacitinib inhibited the production of IFN-γ, TNF-α and the expression of CD25 on T cells from the peripheral blood. In addition, the proliferation and the phosphorylation of STAT1, STAT3, STAT4 by T cells were also depressed. However, tofacitinib had no effect on the secretion of IL-2, the expression of CD69 and the apoptosis of T cells. Conclusion Tofacitinib can inhibit the secretion of IFN-γ and TNF-α by T cells in the peripheral blood, and its mechanism might be related to the inhibitory effect of tofacitinib on the activation, proliferation and signal transduction in T cells.


Assuntos
Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/efeitos dos fármacos , Citocinas/metabolismo , Piperidinas/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Células Cultivadas , Humanos , Interferon gama/metabolismo , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT4/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
8.
BMC Immunol ; 18(1): 38, 2017 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-28724400

RESUMO

BACKGROUND: Interleukin-9 (IL-9) was reported as an active participant in the pathogenesis of allergic asthma. This study aimed to investigate the major source ofIL-9 and its effect on interferon γ (IFN-γ) and immunoglobulin (Ig) secretion by B cells. METHODS: We isolated peripheral blood mononuclear cells from children with allergic asthma and healthy children. IL-9, IL-4 and IFN-γ expression were detected by ELISA, ELISpot and Flowcytometry. Expression of transcription factor PU.1 was measured by Western Blot. We evaluated the effect of IL-9 on B cell activation and Ig production. RESULTS: Results showed that compared with healthy children, levels of IL-9, IL-4 and PU.1 were elevated and levels of IFN-γ were lower in children with allergic asthma. IL-9-expressing CD4+ T cells did not co-express IL-4. Exogenous IL-9 inhibited IFN-γ production in a dose-dependent manner. Antigen-specific Th9 cells existed in children with house dust mite allergic asthma. IL-9 up-regulated expression of CD69 and CD25 on B cells and combination of IL-9 and IL-4 enhanced IgE production. CONCLUSIONS: In conclusion, our results showed that Th9 cells may be the major source of IL-9 in children with allergic asthma. In these patients, IL-9 impairs IFN-γ production and synergistically promotes IL-4-induced IgE secretion.


Assuntos
Asma/imunologia , Interleucina-9/imunologia , Leucócitos Mononucleares/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Adolescente , Animais , Asma/sangue , Células Cultivadas , Criança , Pré-Escolar , Relação Dose-Resposta Imunológica , Feminino , Humanos , Imunoglobulina E/imunologia , Imunoglobulina G/biossíntese , Interferon gama/imunologia , Interleucina-4/imunologia , Leucócitos Mononucleares/citologia , Ativação Linfocitária/imunologia , Masculino , Pyroglyphidae/imunologia , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Auxiliares-Indutores/citologia
9.
Clin Sci (Lond) ; 131(15): 1859-1876, 2017 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-28588103

RESUMO

T-cell responses have been demonstrated to be essential for preventing Mycobacterium tuberculosis infection. The Th1-cytokines produced by T cells, such as INF-γ, IL-2, and TNF-α, not only limit the invasion of M. tuberculosis but also eliminate the pathogen at the site of infection. Bacillus Calmette-Guérin (BCG) is known to induce Th1-type responses but the protection is inadequate. Identification of immunogenic components, in addition to those expressed in BCG, and induction of a broad spectrum of Th1-type responses provide options for generating sufficient adaptive immunity. Here, we studied human pulmonary T-cell responses induced by the M. tuberculosis-specific antigen Rv3615c, a protein with a similar size and sequence homology to ESAT-6 and CFP-10, which induced dominant CD4+ T-cell responses in human tuberculosis (TB) models. We characterized T-cell responses including cytokine profiling, kinetics of activation, expansion, differentiation, TCR usage, and signaling of activation induced by Rv3615c compared with other M. tuberculosis-specific antigens. The expanded CD4+ T cells induced by Rv3615c predominately produced Th1, but less Th2 and Th17, cytokines and displayed effector/memory phenotypes (CD45RO+CD27-CD127-CCR7-). The magnitude of expansion and cytokine production was comparable to those induced by well-characterized the 6 kDa early secreted antigenic target (ESAT-6), the 10 kDa culture filtrate protein (CFP-10) and BCG. Rv3615c contained multiple epitopes Rv3615c1-15, Rv3615c6-20, Rv3615c66-80, Rv3615c71-85 and Rv3615c76-90 that activated CD4+ T cells. The Rv3615c-specific CD4+ T cells shared biased of T-cell receptor variable region of ß chain (TCR Vß) 1, 2, 4, 5.1, 7.1, 7.2 and/or 22 chains to promote their differentiation and proliferation respectively, by triggering a signaling cascade. Our data suggest that Rv3615c is a major target of Th1-type responses and can be a highly immunodominant antigen specific for M. tuberculosis infection.


Assuntos
Antígenos de Bactérias/imunologia , Proteínas de Bactérias/imunologia , Epitopos Imunodominantes/imunologia , Mycobacterium tuberculosis/imunologia , Células Th1/imunologia , Tuberculose Pleural/imunologia , Adulto , Idoso , Linfócitos T CD4-Positivos/imunologia , Estudos de Casos e Controles , Células Cultivadas , Citocinas/biossíntese , Feminino , Humanos , Memória Imunológica/imunologia , Imunofenotipagem , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Derrame Pleural/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Adulto Jovem
10.
Clin Sci (Lond) ; 131(13): 1499-1513, 2017 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-28550144

RESUMO

Interleukin (IL)-9 exerts a variety of functions in autoimmune diseases. However, its role in ischemic brain injury remains unknown. The present study explored the biological effects of IL-9 in ischemic stroke (IS). We recruited 42 patients newly diagnosed with IS and 22 age- and sex-matched healthy controls. The expression levels of IL-9 and percentages of IL-9-producing T cells, including CD3+CD4+IL-9+ and CD3+CD8+IL-9+ cells, were determined in peripheral blood mononuclear cells (PBMCs) obtained from patients and control individuals. We also investigated the effects of IL-9 on the blood-brain barrier (BBB) following oxygen-glucose deprivation (OGD) and the potential downstream signaling pathways. We found that patients with IS had higher IL-9 expression levels and increased percentages of IL-9-producing T cells in their PBMCs. The percentages of CD3+CD4+IL-9+ and CD3+CD8+IL-9+ T cells were positively correlated with the severity of illness. In in vitro experiments using bEnd.3 cells, exogenously administered IL-9 exacerbated the loss of tight junction proteins (TJPs) in cells subjected to OGD plus reoxygenation (RO). This effect was mediated via activation of IL-9 receptors, which increased the level of endothelial nitric oxide synthase (eNOS), as well as through up-regulated phosphorylation of signal transducer and activator of transcription 1 and 3 and down-regulated phosphorylated protein kinase B/phosphorylated phosphatidylinositol 3-kinase signaling. These results indicate that IL-9 has a destructive effect on the BBB following OGD, at least in part by inducing eNOS production, and raise the possibility of targetting IL-9 for therapeutic intervention in IS.


Assuntos
Barreira Hematoencefálica/imunologia , Interleucina-9/imunologia , Acidente Vascular Cerebral/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Complexo CD3/sangue , Estudos de Casos e Controles , Hipóxia Celular/fisiologia , Células Cultivadas , Proteínas de Ligação a DNA/sangue , Proteínas de Ligação a DNA/genética , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Feminino , Expressão Gênica , Glucose/metabolismo , Fatores de Troca do Nucleotídeo Guanina/sangue , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Interleucina-9/sangue , Interleucina-9/genética , Interleucina-9/farmacologia , Masculino , Camundongos , Pessoa de Meia-Idade , Óxido Nítrico Sintase Tipo III/biossíntese , Proteínas Nucleares/sangue , Proteínas Nucleares/genética , Proteínas Proto-Oncogênicas/sangue , Proteínas Proto-Oncogênicas/genética , RNA Mensageiro/genética , Índice de Gravidade de Doença , Acidente Vascular Cerebral/patologia , Subpopulações de Linfócitos T/imunologia , Proteínas de Junções Íntimas/metabolismo , Transativadores/sangue , Transativadores/genética , Adulto Jovem
11.
Clin Sci (Lond) ; 131(4): 297-308, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-27923881

RESUMO

The translocator protein (TSPO) ligands affected inflammatory and immune responses. However, the exact effects of TSPO ligands on Th1 responses in vitro and in vivo are still unclear. In the present study, we found that TSPO ligands, FGIN1-27 and Ro5-4864, suppressed the cytokine production in a dose-dependent manner by purified human CD4+ T-cells from peripheral blood mononuclear cells (PBMCs) after stimulation. TSPO ligands inhibited the production of interferon γ (IFN-γ) by memory CD4+ T-cells and the differentiation of naïve CD4+ T-cells into Th1 cells via suppressing the activity of the corresponding transcription factors as indicated by reduced expression of T-bet and down-regulation of STAT1, STAT4 and STAT5 phosphorylation. TSPO ligands suppressed cell proliferation and activation of CD4+ T-cells by the inhibition of TCR signal transduction including membrane proteins: Zap, Lck, Src; cytoplasm proteins: Plcγ1, Slp-76, ERK, JNK and the nucleoproteins: c-Jun and c-Fos. In addition, FGIN1-27 inhibited mixed lymphocyte reactions by human or murine cells. After the transplantation of allogeneic murine skin, injection of FGIN1-27 into mice prevented graft rejection by inhibition of cell infiltration and IFN-γ production. Taken together, our data suggest that TSPO ligands inhibit Th1 cell responses and might be novel therapeutic medicine for the treatment of autoimmune diseases and prevention of transplant rejection.


Assuntos
Rejeição de Enxerto/prevenção & controle , Ácidos Indolacéticos/uso terapêutico , Transplante de Pele , Células Th1/imunologia , Adolescente , Adulto , Animais , Benzodiazepinonas/imunologia , Linfócitos T CD4-Positivos/imunologia , Células Cultivadas , Citocinas/biossíntese , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Rejeição de Enxerto/imunologia , Humanos , Ácidos Indolacéticos/imunologia , Ligantes , Ativação Linfocitária/imunologia , Teste de Cultura Mista de Linfócitos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Fosforilação/imunologia , Receptores de GABA/metabolismo , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/imunologia , Proteínas com Domínio T/metabolismo , Adulto Jovem
12.
Int J Mol Sci ; 17(8)2016 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-27490531

RESUMO

Different cell types possess different miRNA expression profiles, and cell/tissue/organ-specific miRNAs (or profiles) indicate different diseases. Circulating miRNA is either actively secreted by living cells or passively released during cell death. Circulating cell/tissue/organ-specific miRNA may serve as a non-invasive biomarker for allo- or xeno-transplantation to monitor organ survival and immune rejection. In this review, we summarize the proof of concept that circulating organ-specific miRNAs serve as non-invasive biomarkers for a wide spectrum of clinical organ-specific manifestations such as liver-related disease, heart-related disease, kidney-related disease, and lung-related disease. Furthermore, we summarize how circulating organ-specific miRNAs may have advantages over conventional methods for monitoring immune rejection in organ transplantation. Finally, we discuss the implications and challenges of applying miRNA to monitor organ survival and immune rejection in allo- or xeno-transplantation.


Assuntos
Biomarcadores/sangue , Cardiopatias/diagnóstico , Nefropatias/diagnóstico , Hepatopatias/diagnóstico , MicroRNAs/genética , Cardiopatias/sangue , Cardiopatias/genética , Humanos , Nefropatias/sangue , Nefropatias/genética , Hepatopatias/sangue , Hepatopatias/genética , MicroRNAs/sangue , Transplante Heterólogo , Transplante Homólogo
13.
Sci Rep ; 6: 30362, 2016 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-27468819

RESUMO

Although CD4(+) T cells are recognized to play an important role in the inflammatory response of nasal polyps (NPs), the biological functions of CD8(+) T cells in polypogenesis remain unclear. In this study, we analyzed cell markers, cytokine expression and transcription factors in IL-21-expressing CD8(+) T cells in polyp tissues of NP patients. The results showed that the majority of IL-21-producing CD8(+) T cells were effector memory cells and they co-expressed IFN-γ. IL-21-expressing CD8(+) T cells in polyp tissues expressed higher CXCR5, PD-1, and ICOS levels than cells in control tissues and showed significantly higher T-bet and Bcl-6 expression levels compared with IL-21(-)CD8(+) T cells. Purified polyp CD8(+) T cells promoted IgG production from isolated polyp B cells in vitro, and recombinant IL-12 modulated the expression of IL-21, IFN-γ and CD40L in purified polyp CD8(+) T cells. Moreover, the percentage of IL-21(+)CD8(+) T cells in polyp tissues was positively correlated with endoscopic and CT scan scores in NP patients. These findings indicated that polyp CD8(+) T cells, by co-expressing IL-21 and IFN-γ and other markers, display a Tfh cell functionality, which is associated with the clinical severity of NP patients.


Assuntos
Linfócitos T CD8-Positivos/metabolismo , Interleucinas/metabolismo , Pólipos Nasais/metabolismo , Adolescente , Adulto , Idoso , Linfócitos B/metabolismo , Ligante de CD40/metabolismo , Estudos de Casos e Controles , Separação Celular , Feminino , Citometria de Fluxo , Humanos , Imunoglobulina G/metabolismo , Interferon gama/metabolismo , Interleucina-17/metabolismo , Masculino , Pessoa de Meia-Idade , Fenótipo , Receptores CXCR5/metabolismo , Proteínas Recombinantes/metabolismo , Adulto Jovem
14.
Immunology ; 149(1): 25-34, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27242265

RESUMO

Schistosoma japonicum infection can induce granulomatous inflammation and cause tissue damage in the mouse liver. The cytokine secretion profile of T helper (Th) cells depends on both the nature of the activating stimulus and the local microenvironment (e.g. cytokines and other soluble factors). In the present study, we found an accumulation of large numbers of IFN-γ(+)  IL-4(+)  CD4(+) T cells in mouse livers. This IFN-γ(+)  IL-4(+) cell population increased from 0·68 ± 0·57% in uninfected mice to 7·05 ± 3·0% by week 4 following infection and to 9·6 ± 5·28% by week 6, before decreasing to 6·3 ± 5·9% by week 8 in CD4 T cells. Moreover, IFN-γ(+)  IL-4(+) Th cells were also found in mouse spleen and mesenteric lymph nodes 6 weeks after infection. The majority of the IFN-γ(+)  IL-4(+) Th cells were thought to be related to a state of immune activation, and some were memory T cells. Moreover, we found that these S. japonicum infection-induced IFN-γ(+)  IL-4(+) cells could express interleukin-2 (IL-2), IL-9, IL-17 and high IL-10 levels at 6 weeks after S. japonicum infection. Taken together, our data suggest the existence of a population of IFN-γ(+)  IL-4(+) plasticity effector/memory Th cells following S. japonicum infection in C57BL/6 mice.


Assuntos
Fígado/imunologia , Schistosoma japonicum/imunologia , Esquistossomose Japônica/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Diferenciação Celular , Células Cultivadas , Feminino , Memória Imunológica , Interferon gama/metabolismo , Interleucina-4/metabolismo , Fígado/parasitologia , Camundongos , Camundongos Endogâmicos C57BL , Equilíbrio Th1-Th2
15.
PLoS One ; 11(3): e0151721, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27031950

RESUMO

Our previous result indicated that memory-like human natural killer (NK) cells from TB pleural fluid cells (PFCs) produced large amounts of IFN-γ in response to Bacille Calmette Guerin (BCG). Furthermore, recent studies have shown that human lymphoid tissues harbored a unique NK cell subset that specialized in production of interleukin (IL)-22, a proinflammatory cytokine that mediates host defense against pathogens. Yet little information was available with regard to the properties of IL-22 production by memory-like human NK cells. In the present study, we found that cytokines IL-15 induced and IL-12 enhanced the levels of IL-22 by NK cells from TB PFCs. In addition, IL-22 but not IL-17 was produced by NK cells from PFCs in response to BCG and M.tb-related Ags. More importantly, the subset of specific IL-22-producing NK cells were distinct from IFN-γ-producing NK cells in PFCs. CD45RO+ or CD45RO- NK cells were sorted, co-cultured with autologous monocytes and stimulated with BCG for the production of IL-22. The result demonstrated that CD45RO+ but not CD45RO- NK cells produced significantly higher level of IL-22. Anti-IL-12Rß1 mAbs (2B10) partially inhibit the expression of IL-22 by NK cells under the culture with BCG. Consistently, BCG specific IL-22-producing NK cells from PFCs expressed CD45ROhighNKG2Dhighgranzyme Bhigh. In conclusion, our data demonstrated that memory-like antigen-specific CD45RO+ NK cells might participate in the recall immune response for M. tb infection via producing IL-22, which display a critical role to fight against M. tb.


Assuntos
Antígenos de Bactérias/imunologia , Interleucina-15/imunologia , Interleucinas/imunologia , Células Matadoras Naturais/imunologia , Tuberculose Pleural/imunologia , Adulto , Idoso , Antígenos de Bactérias/farmacologia , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Humanos , Memória Imunológica/imunologia , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-12/imunologia , Interleucina-12/farmacologia , Interleucina-15/farmacologia , Interleucinas/metabolismo , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/metabolismo , Antígenos Comuns de Leucócito/imunologia , Antígenos Comuns de Leucócito/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Tuberculose Pleural/metabolismo , Adulto Jovem
16.
PLoS One ; 11(1): e0147356, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26785168

RESUMO

In the current study of Mycobacterium tuberculosis (MTB)-specific T and B cells, we found that MTB-specific peptides from early secreted antigenic target-6 (ESAT-6) and culture filtrate protein-10 (CFP-10) induced the expression of IL-21 predominantly in CD4(+) T cells. A fraction of IL-21-expressing CD4(+) T cells simultaneously expressed Th1 cytokines but did not secrete Th2 or Th17 cytokines, suggesting that MTB-specific IL-21-expressing CD4(+) T cells were different from Th1, Th2 and Th17 subpopulations. The majority of MTB-specific IL-21-expressing CD4(+) T cells co-expressed IFN-γ and IL-21+IFN-γ(+)CD4(+) T cells exhibited obviously polyfunctionality. In addition, MTB-specific IL-21-expressing CD4(+) T cells displayed a CD45RO+CD62Ll(ow)CCR7(low)CD40L(high)ICOS(high) phenotype. Bcl-6-expression was significantly higher in IL-21-expressing CD4(+) T cells than IL-21-CD4(+) T cells. Moreover, IL-12 could up-regulate MTB-specific IL-21 expression, especially the frequency of IL-21(+)IFN-γ+CD4(+) T cells. Taken together, our results demonstrated that MTB-specific IL-21(+)IFN-γ(+)CD4(+) T cells from local sites of tuberculosis (TB) infection could be enhanced by IL-12, which have the features of both Tfh and Th1 cells and may have an important role in local immune responses against TB infection.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Interferon gama/imunologia , Interleucina-12/farmacologia , Interleucinas/imunologia , Mycobacterium tuberculosis/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Tuberculose/imunologia , Adulto , Idoso , Inibidores da Angiogênese/farmacologia , Feminino , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia , Adulto Jovem
17.
Cell Cycle ; 14(21): 3362-72, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26566861

RESUMO

Interleukine-12 is critical for the differentiation of Th1 cells and can improve the development of Th1 cells with Tfh cell features in mouse model. Human effector CD4(+) T cells also exhibit poly-functionality by co-expressing IL-21 and IFN-γ. However, the effects of IL-12 on regulating generation of human IL-21- and IFN-γ-expressing CD4(+) T cells are still incompletely understood. Our studies found that IL-12 but not IL-21 could induce the differentiation of human naive CD4(+) T cells into multi-cytokine expressing CD4(+) T cells in vitro, which co-expressed IL-21 and IFN-γ with or without IL-2 and TNF-α. At early stage of differentiation, addition of excess exogenous IFN-γ could increase the generation of IL-21- and IFN-γ-expressing CD4(+) T cells, furthermore, anti-IFN-γ depressed the percentage of poly-functional CD4(+) T cells. Phenotypically, IL-21(+)IFN-γ(+)CD4(+) T cells exhibited more characteristic features about both of Th1 and Tfh cells than IL-21 or IFN-γ single-expressing CD4(+) T cells. Mechamistically, IL-12 modulated the differentiation of IL-21(+)IFN-γ(+)CD4(+) T cells from naive CD4(+) T cells via the pathways of STAT-1/4, T-bet and BCL(-)6. Different from naive CD4(+) T cells, IL-12 increasing the generation of IL-21(+)IFN-γ(+)CD4(+) T cells from memory CD4(+) T cells was only involved in STAT-4 pathway but not STAT-1. Poly-functional CD4(+) T cells were contributed to generation and progress of varies diseases and our studies provide basic theoretics for the designs of vaccine and therapies of diseases.


Assuntos
Linfócitos T CD4-Positivos/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Interferon gama/metabolismo , Interleucina-12/farmacologia , Interleucinas/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Células Cultivadas , Proteínas de Ligação a DNA/metabolismo , Sangue Fetal/citologia , Humanos , Memória Imunológica , Recém-Nascido , Interferon gama/imunologia , Interferon gama/farmacologia , Interleucinas/imunologia , Interleucinas/farmacologia , Cinética , Fenótipo , Proteínas Proto-Oncogênicas c-bcl-6 , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT4/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas com Domínio T/metabolismo , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th1/metabolismo , Regulação para Cima
18.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 31(11): 141-1446, 2015 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-26522348

RESUMO

OBJECTIVE: To investigate the secretion of IL-12p40 and IL-6 by splenocytes, dendritic cells stimulated by different Toll-like receptor (TLR) agonists or in the sera of mice immunized with different TLR agonists, and evaluate the effects of different TLR agonists on the function of T helper (Th) cells, especially the differentiation of Th1 cells. METHODS: Supernatants of splenocytes and dendritic cells stimulated with different TLR agonists for 24 hours or sera of mice immunized with different TLR agonists at different time points were used to determine the levels of IL-12p40 and IL-6 by ELISA. CD4⁺ T cells isolated from the spleens of ovalbumin-T cell receptor (OVA-TCR) transgenic BALB/c (DO11.10) mice were co-cultured with antigen presenting cells (APCs) from congenic BALB/c mice at 1:3 ratio of T:APCs. Cultures were stimulated with OVA peptide or OVA peptide plus different doses of TLR agonists and the supernatants collected at different time points were assayed by ELISA for detecting IFN-γ. RESULTS: Pam3CSK4, R848 and CpG oligodeoxynucleotide (ODN) promoted the production of IL-12p40 and IL-6 by splenocytes and dendritic cells obviously, and induced the expression of IFN-γ in antigen specific CD4⁺ T cells in a time- and dose-dependent manner. Monophosphoryl lipid A from Salmonella minnesota R595 lipopolysaccharide (MPLA-SM) induced low levels of cytokines by splenocytes and couldn't promote the production of IFN-γ by antigen specific CD4⁺ T cells, but increased the expressions of IL-12p40 and IL-6 by DCs. All the sera of mice immunized with the four TLR agonists expressed high levels of IL-12p40 and IL-6. CONCLUSION: Splenocytes, DCs stimulated or sera of mice immunized with different TLR agonists produced different levels of cytokines, which could further affect the differentiation of Th1 cells.


Assuntos
Linfócitos T Auxiliares-Indutores/imunologia , Receptores Toll-Like/agonistas , Animais , Feminino , Interferon gama/biossíntese , Subunidade p40 da Interleucina-12/sangue , Interleucina-6/sangue , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/imunologia
19.
Immunogenetics ; 67(11-12): 629-39, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26409833

RESUMO

X-linked severe combined immunodeficiency (X-SCID) is one of the most common causes of primary immunodeficiencies in humans. A 4-month-old boy with recurrent pulmonary infection had decreased numbers of CD3(+), CD4(+), CD8(+) T lymphocytes, and NK cells and increased levels of CD19(+) B cells but no memory B cells or plasma cells. The production of cytokines by T cells and the activation of T and B cells were either absent or inefficient. While B cell levels were high, they were all IgM-positive, and the secretion of all Ig isotypes by activated B cells in vitro was defective. Genomic DNA sequencing revealed that the patient had missense mutations in the IL2RG (exon 5, 718 T > C) and IL7R genes (exon 2, 197 T > C; exon 4, 412G > A). Although the patient's father and one of his sisters have the same missense homozygous mutations of the IL7R gene, neither of them exhibited the immunological phenotype of SCID. The results indicate that the IL2RG gene mutation or a combination of the IL7R and IL2RG mutations in the sick boy had resulted in T(-)NK(-)B(+) SCID.


Assuntos
Linfócitos B/imunologia , Subunidade gama Comum de Receptores de Interleucina/genética , Células Matadoras Naturais/imunologia , Mutação/genética , Linfócitos T/imunologia , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/genética , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/imunologia , Feminino , Humanos , Lactente , Subunidade gama Comum de Receptores de Interleucina/imunologia , Ativação Linfocitária , Masculino , Linhagem , Fenótipo , Prognóstico
20.
Oncotarget ; 6(30): 28633-45, 2015 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-26416419

RESUMO

Natural killer T (NKT) cells from mouse and human play an important role in the immune responses against Mycobacterium tuberculosis. However, the function of CD3(+)TCRvß11(+) NKT cells at the local site of M. tuberculosis infection remains poorly defined. In the present study, we found that after stimulation with M. tuberculosis antigens, NKT cells isolated from tuberculosis (TB) pleural fluid mononuclear cells (PFMCs) produced IL-21 and other cytokines including IFN-γ, TNF-α, IL-2 and IL-17. IL-21-expressing NKT cells in PFMCs displayed effector memory phenotype, expressing CD45RO(high)CD62L(low)CCR7(low). Moreover, NKT cells expressed high levels of CXCR5 and all of IL-21-expressing NKT cells co-expressed CXCR5. The frequency of BCL-6-expression was higher in IL-21-expressing but not in non-IL-21-expressing CD3(+)TCRvß11(+) NKT cells. Sorted CD3(+)TCRvß11(+) NKT cells from PFMCs produced IFN-γ and IL-21 after stimulation, which expressed CD40L. Importantly, CD3(+)TCRvß11(+) NKT cells provided help to B cells for the production of IgG and IgA. Taken together, our data demonstrate that CD3(+)TCRvß11(+) NKT cells from a local site of M. tuberculosis infection produce IL-21, express CXCR5 and CD40L, help B cells to secrete IgG and IgA, and may participate in local immune responses against M. tuberculosis infection.


Assuntos
Antígenos de Bactérias/imunologia , Linfócitos B/imunologia , Imunoglobulina A Secretora/imunologia , Imunoglobulina G/imunologia , Interleucinas/imunologia , Mycobacterium tuberculosis/imunologia , Células T Matadoras Naturais/imunologia , Tuberculose Pleural/imunologia , Adulto , Idoso , Antígenos de Bactérias/metabolismo , Linfócitos B/metabolismo , Linfócitos B/microbiologia , Complexo CD3/imunologia , Ligante de CD40/imunologia , Separação Celular/métodos , Células Cultivadas , Feminino , Citometria de Fluxo , Humanos , Imunoglobulina A Secretora/metabolismo , Imunoglobulina G/metabolismo , Memória Imunológica , Imunofenotipagem , Interleucinas/metabolismo , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/metabolismo , Células T Matadoras Naturais/metabolismo , Células T Matadoras Naturais/microbiologia , Comunicação Parácrina , Fenótipo , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Receptores CXCR5/imunologia , Transdução de Sinais , Tuberculose Pleural/metabolismo , Tuberculose Pleural/microbiologia , Adulto Jovem
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