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1.
Cell Host Microbe ; 27(3): 467-475.e6, 2020 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-32075742

RESUMEN

Fecal IgA production depends on colonization by a gut microbiota. However, the bacterial strains that drive gut IgA production remain largely unknown. Here, we assessed the IgA-inducing capacity of a diverse set of human gut microbial strains by monocolonizing mice with each strain. We identified Bacteroides ovatus as the species that best induced gut IgA production. However, this induction varied bimodally across different B. ovatus strains. The high IgA-inducing B. ovatus strains preferentially elicited more IgA production in the large intestine through the T cell-dependent B cell-activation pathway. Remarkably, a low-IgA phenotype in mice could be robustly and consistently converted into a high-IgA phenotype by transplanting a multiplex cocktail of high IgA-inducing B. ovatus strains but not individual ones. Our results highlight the critical importance of microbial strains in driving phenotype variation in the mucosal immune system and provide a strategy to robustly modify a gut immune phenotype, including IgA production.


Asunto(s)
Bacteroides/clasificación , Heces , Microbioma Gastrointestinal , Inmunoglobulina A/inmunología , Intestino Grueso/inmunología , Animales , Linfocitos B/inmunología , Bacteroides/inmunología , Linfocitos T CD4-Positivos/inmunología , Vida Libre de Gérmenes , Humanos , Intestino Grueso/microbiología , Ratones , Ratones Endogámicos C57BL
2.
Medicine (Baltimore) ; 99(2): e18367, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31914015

RESUMEN

Little is known about the decay kinetics of interferon (IFN)-γ response and its influencing factors in tuberculous pleurisy. We enrolled thirty-two patients with tuberculous pleurisy prospectively and followed up at month 0, 6, and 9, at which time peripheral venous blood was drawn for interferon gamma release assay (IGRA) by means of QuantiFERON-TB Gold In-Tube (QFT-GIT). Demographic and clinical data were captured. To identify significant predictive factors influencing the IFN-γ response, multiple linear regression analyses were performed. Percentage of CD4+, CD8+, Vγ2Vδ2 T cells and Treg cells were measured by flow cytometry. The percentage of QFT-GIT-positive patients at baseline, month 6 and month 9 were 96.9% (30/32), 90.6% (29/32) and 84.4% (27/32), respectively. Quantitative IFN-γ response at baseline were significantly correlated with symptom duration (P = .003, R = 0.261) and age (P = .041, R = 0.132). Besides, the decreases of the IFN-γ response at month 6 and month 9 were positively correlated with the IFN-γ level at baseline. The dynamic tendency of the percentages of Treg cells was similar to the IFN-γ responses at each time-point. Quantitative IFN-γ response could be influenced by host immune status, instead of disease burden and anti-tuberculosis treatment. IGRA is probably not a useful biomarker of treatment efficacy in tuberculous pleurisy.


Asunto(s)
Ensayos de Liberación de Interferón gamma/métodos , Interferón gamma/inmunología , Tuberculosis Pleural/sangre , Adulto , Antituberculosos/administración & dosificación , Antituberculosos/uso terapéutico , Linfocitos T CD4-Positivos/inmunología , Femenino , Citometría de Flujo/métodos , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Linfocitos T/inmunología , Tuberculosis Pleural/diagnóstico , Tuberculosis Pleural/tratamiento farmacológico , Tuberculosis Pleural/metabolismo
3.
Medicine (Baltimore) ; 99(1): e18462, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31895778

RESUMEN

Proinflammatory interleukin-26 (IL-26) is involved in chronic inflammation; however, the role of IL-26 in chronic hepatitis B (CHB) remains unknown.In this study, serum IL-26 was quantified in a cohort of CHB patients at baseline and during telbivudine (LdT) treatment.Our results showed that the serum IL-26 level was significantly elevated in CHB patients compared with that in healthy controls and was time-dependently decreased during LdT treatment, accompanying hepatitis B e antigen (HBeAg) seroconversion and reduced serum levels of hepatitis B virus (HBV) DNA, aspartate transaminase, and alanine transaminase across baseline and treatment. In addition, the serum level of IL-26 exhibited a similar declining trend to that of T helper 17 (Th17) cell-secreted IL-17 during LdT treatment in CHB patients. The percentage of IL-26-expressing CD4 cells was significantly higher than that of IL-26-expressing CD4 cells isolated from the peripheral blood mononuclear cells of CHB patients, suggesting that serum IL-26 might be mainly released from CD4 T cells. Furthermore, the baseline mRNA levels of IL-26 and orphan nuclear receptor RORγt-an important transcription factor expressed by Th17 cells-were positively correlated and displayed the same declining trend across the baseline and LdT treatment in CHB patients, suggesting that Th17 cells could be a possible cellular source of the increased serum IL-26 in CHB patients.Taken together, our results suggest that serum IL-26, possibly produced by Th17 CD4 cells, is a novel and potential biomarker for CHB prognosis and treatment.


Asunto(s)
Virus de la Hepatitis B/inmunología , Hepatitis B Crónica/sangre , Hepatitis B Crónica/inmunología , Interleucinas/sangre , Adulto , Antivirales/uso terapéutico , Linfocitos T CD4-Positivos/inmunología , Estudios de Casos y Controles , Ensayo de Inmunoadsorción Enzimática , Femenino , Hepatitis B Crónica/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana Edad , Telbivudina/uso terapéutico , Células Th17/inmunología , Adulto Joven
4.
Nat Commun ; 11(1): 155, 2020 01 09.
Artículo en Inglés | MEDLINE | ID: mdl-31919358

RESUMEN

Dysregulated hematopoiesis occurs in several chronic inflammatory diseases, but it remains unclear how hematopoietic stem cells (HSCs) in the bone marrow (BM) sense peripheral inflammation and contribute to tissue damage in arthritis. Here, we show the HSC gene expression program is biased toward myelopoiesis and differentiation skewed toward granulocyte-monocyte progenitors (GMP) during joint and intestinal inflammation in experimental spondyloarthritis (SpA). GM-CSF-receptor is increased on HSCs and multipotent progenitors, favoring a striking increase in myelopoiesis at the earliest hematopoietic stages. GMP accumulate in the BM in SpA and, unexpectedly, at extramedullary sites: in the inflamed joints and spleen. Furthermore, we show that GM-CSF promotes extramedullary myelopoiesis, tissue-toxic neutrophil accumulation in target organs, and GM-CSF prophylactic or therapeutic blockade substantially decreases SpA severity. Surprisingly, besides CD4+ T cells and innate lymphoid cells, mast cells are a source of GM-CSF in this model, and its pathogenic production is promoted by the alarmin IL-33.


Asunto(s)
Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Hematopoyesis Extramedular/fisiología , Células Madre Hematopoyéticas/metabolismo , Mielopoyesis/fisiología , Espondiloartritis/patología , Animales , Linfocitos T CD4-Positivos/inmunología , Diferenciación Celular , Células Cultivadas , Femenino , Interleucina-33/inmunología , Mastocitos/inmunología , Ratones , Ratones Endogámicos BALB C , Espondiloartritis/inmunología
5.
Photochem Photobiol Sci ; 19(2): 171-179, 2020 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-31942903

RESUMEN

Nicotinamide (NAM), an amide form of vitamin B3, replenishes cellular energy after ultraviolet radiation (UVR) exposure, thereby enhancing DNA repair and reducing UVR's immunosuppressive effects. NAM reduces actinic keratoses and new keratinocyte cancers in high risk individuals, but its effects on melanoma are unknown. Melanomas arising on NAM or placebo within the ONTRAC skin cancer chemoprevention trial (Oral Nicotinamide To Reduce Actinic Cancer) were examined by immunohistochemistry. The effects of NAM (50 µM, 5 mM and 20 mM) on the viability, proliferation and invasiveness of four human melanoma cell lines and on the viability and proliferation of two human melanocyte lines, with and without UV irradiation were also investigated. 50 µM NAM did not affect viability, proliferation or invasion of melanoma or melanocyte cell lines, whereas concentrations too high to be achievable in vivo reduced viability and proliferation. Nicotinamide did not enhance melanoma viability, proliferation or invasiveness in vitro, providing additional confidence in its safety for use in clinical trials in high risk patients. Peritumoral and tumour infiltrating CD4+ and CD8+ lymphocytes were significantly increased in melanomas arising on NAM compared to those arising on placebo. Given the chemopreventive activity of nicotinamide against keratinocyte cancers, its DNA repair enhancing effects in melanocytes and now its potential enhancement of tumour-infiltrating lymphocytes and lack of adverse effects on melanoma cell growth and proliferation, clinical trials of nicotinamide for melanoma chemoprevention are now indicated.


Asunto(s)
Melanoma/patología , Niacinamida/farmacología , Neoplasias Cutáneas/patología , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Humanos , Melanoma/tratamiento farmacológico , Melanoma/prevención & control , Niacinamida/química , Niacinamida/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológico , Rayos Ultravioleta
6.
BMC Infect Dis ; 20(1): 58, 2020 Jan 17.
Artículo en Inglés | MEDLINE | ID: mdl-31952516

RESUMEN

BACKGROUND: Cytomegalovirus (CMV) infection is one of the most common opportunistic infections following organ transplantation, despite administration of CMV prophylaxis. CMV-specific T-cell immunity (TCI) has been associated with reduced rates of CMV infection. We describe for the first time clinical experience using the CMV T-Cell Immunity Panel (CMV-TCIP), a commercially available assay which measures CMV-specific CD4+ and CD8+ T-cell responses, to predict clinically significant CMV events. METHODS: Adult (> 18-year-old) patients with CMV-TCIP results and ≥ 1 subsequent assessment for CMV DNAemia were included at Brown University and the University of Maryland Medical Center-affiliated hospitals between 4/2017 and 5/2019. A clinically significant CMV event was defined as CMV DNAemia prompting initiation of treatment. We excluded indeterminate results, mostly due to background positivity, allogeneic hematopoetic cell transplant (HCT) recipients, or patients who were continued on antiviral therapy against CMV irrespective of the CMV-TCIP result, because ongoing antiviral therapy could prevent a CMV event. RESULTS: We analyzed 44 samples from 37 patients: 31 were solid organ transplant recipients, 4 had hematologic malignancies, 2 had autoimmune disorders. The CMV-protection receiver operating characteristic (ROC) area under the curve (AUC) was significant for %CMV-specific CD4+ (AUC: 0.78, P < 0.001) and borderline for CD8+ (AUC: 0.66, P = 0.064) T-cells. At a cut-off value of 0.22% CMV-specific CD4+ T-cells, positive predictive value (PPV) for protection against CMV was 85% (95%CI 65-96%), and negative predictive value (NPV) was 67% (95%CI 41-87%). CONCLUSIONS: The CMV-TCIP, in particular %CMV-specific CD4+ T-cells, showed good diagnostic performance to predict CMV events. The CMV-TCIP may be a useful test in clinical practice, and merits further validation in larger prospective studies.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Citomegalovirus/inmunología , Inmunoensayo/métodos , Adulto , Anciano , Área Bajo la Curva , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/metabolismo , Citocinas/metabolismo , Citomegalovirus/aislamiento & purificación , Infecciones por Citomegalovirus/complicaciones , Infecciones por Citomegalovirus/diagnóstico , Femenino , Citometría de Flujo , Neoplasias Hematológicas/complicaciones , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/virología , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Trasplante de Órganos , Curva ROC , Estudios Retrospectivos
7.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 51(1): 1-6, 2020 Jan.
Artículo en Chino | MEDLINE | ID: mdl-31950781

RESUMEN

Objective: To construct a recombinant Listeria ivanovii (LI) strain that expressed Mycobacterium tuberculosis (MTB) specific antigen protein as a novel multistage tuberculosis (TB) vaccine candidate, and evaluate the biosafety and immunogenicity in mouse model. Methods: T cell epitopes of four genes related to different stages of MTB infection were fused in series to form an antigen gene, i.e. the multistage antigen gene (named msv). Then msv was inserted into the targeting plasmid that contained LI homologous sequences. Recombinant LI strain was obtained by transfecting LI with targeting plasmid and screening the recombinant LI strain that carried msv in the genome after series of homologous gene recombination processes. The growth rate of the recombinant LI strain in vitro was observed and the expression of target protein was verified by Western blot. The 50% lethal dose (LD 50) of the recombinant strain to C57BL/6 mice was measured. Mice were intravenously inoculated with vaccine candidate in dose of 0.1×LD 50.The serum alanine aminotransferase (ALT) levels, bacterial load in organs, and organ pathological sections before and 1, 2, 3, 5, 7, 14 d after vaccination were used to evaluate the safety of vaccine candidate strain. To analyze the immunogenicity of vaccine candidate strain, mice were intravenously inoculated with LI- msv, LI, and NS respectively. Nine days post immunization, the spleens were isolated under sterile conditions and splenocytes were collected and stimulated. Lyphocytes which secret specific cytokines, interferon (IFN)-γ, tumor necrosis factor (TNF)-α and interleukin (IL)-2 were analyzed by flow cytometry. Results: A recombinant strain named LI- msv which was capable of expressing the multistage TB antigen protein was successfully constructed. The LD 50 value of LI- msv for C57BL/6 mice (i.v.) was 3.3×10 8 CFU. After intravenously immunized the mice, this strain mainly multiplied in the liver and spleen, and was cleared at 7 d post innoculation. Such infection process caused transient pathological damages of the liver and spleen. Results of flow cytometry showed specific IFN-γ + CD4 + and IFN-γ + CD8 +T lymphocytes were successfully induced in LI -msv immunized mice spleen lymphocytes. The frequency of IFN-γ positive CD4 + and CD8 +T cells was significantly higher than those of vector control group and NS control group ( P<0.005). Additionally, the frequency of specific TNF-α + CD4 + T cell in LI -msv immunized group was significantly higher than that of vector control ( P<0.01) and NS control group ( P<0.005), and TNF-α + CD8 + T cell frequency obviously increased than NS control group ( P<0.005). Conclusions: A novel multistage TB vaccine candidate expressing TB multistage antigen based on LI was successfully constructed. This vaccine candidate is safe and can induce specific cellular immune response to some extent. It is promising to be further studied as a candidate vaccine against tuberculosis.


Asunto(s)
Antígenos Bacterianos , Listeria , Mycobacterium tuberculosis , Vacunas contra la Tuberculosis , Tuberculosis/prevención & control , Animales , Antígenos Bacterianos/genética , Antígenos Bacterianos/inmunología , Linfocitos T CD4-Positivos/inmunología , Inmunidad Celular/inmunología , Listeria/genética , Ratones , Ratones Endogámicos C57BL , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/inmunología , Proteínas Recombinantes/genética , Proteínas Recombinantes/inmunología , Tuberculosis/inmunología , Vacunas contra la Tuberculosis/genética , Vacunas contra la Tuberculosis/normas
8.
Cancer Sci ; 111(1): 23-35, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31660687

RESUMEN

Chemoradiotherapy (CRT) is the standard neoadjuvant therapy for locally advanced rectal cancer (RC). However, neoadjuvant chemotherapy (NAC) also shows favorable outcomes. Although the immunological environment of RC has been thoroughly discussed, the effect of NAC on it is less clear. Here, we investigated the immunological microenvironment, including T cell infiltration, activation, and topological distribution, of resected RC tissue after neoadjuvant therapies and evaluated the correlation between T cell subsets and patient prognosis. Rectal cancer patients (n = 188) were enrolled and categorized into 3 groups, namely CRT (n = 41), NAC (n = 46), and control (surgery alone; n = 101) groups. Characterization of residual carcinoma cells and T cell subsets in resected tissues was performed using multiplex fluorescence immunohistochemistry. The densities of total and activated (Ki67high ) T cells in tissues after NAC, but not CRT, were higher than in control. In both CRT and NAC groups, patients presenting with higher treatment effects showed aggressive infiltration of T cell subsets into carcinomas. Multivariate analyses of pathological and immunological features and prognosis revealed that carcinoma Ki67high CD4+ T cells after CRT and stromal Ki67high CD8+ T cells after NAC are important prognostic factors, respectively. Our results suggest that evaluation of T cell activation with Ki67 expression and its tumor localization can be used to determine the prognosis of advanced RC after neoadjuvant therapies.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Antígeno Ki-67/metabolismo , Neoplasias del Recto/inmunología , Neoplasias del Recto/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/metabolismo , Quimioradioterapia/métodos , Femenino , Humanos , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante/métodos , Pronóstico , Neoplasias del Recto/tratamiento farmacológico , Microambiente Tumoral/inmunología
9.
Immunogenetics ; 72(1-2): 85-88, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31735991

RESUMEN

Celiac disease is caused by an abnormal intestinal T cell response to cereal gluten proteins. The disease has a strong human leukocyte antigen (HLA) association, and CD4+ T cells recognizing gluten epitopes presented by disease-associated HLA-DQ allotypes are considered to be drivers of the disease. This paper provides an update of the currently known HLA-DQ restricted gluten T cell epitopes with their names and sequences.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Enfermedad Celíaca/inmunología , Epítopos de Linfocito T/inmunología , Glútenes/inmunología , Complejo Mayor de Histocompatibilidad/inmunología , Animales , Humanos , Terminología como Asunto
10.
Infect Immun ; 88(2)2020 01 22.
Artículo en Inglés | MEDLINE | ID: mdl-31740528

RESUMEN

Influenza A virus (H1N1) is an acute, highly contagious respiratory virus. The use of lactic acid bacteria (LAB) to deliver mucosal vaccines against influenza virus infection is a research hot spot. In this study, two recombinant Lactobacillus plantarum strains expressing hemagglutinin (HA) alone or coexpressing aCD11c-HA to target HA protein to dendritic cells (DCs) by fusion to an anti-CD11c single-chain antibody (aCD11c) were constructed. The activation of bone marrow dendritic cells (BMDCs) by recombinant strains and the interaction of activated BMDCs and sorted CD4+ or CD8+ T cells were evaluated through flow cytometry in vitro, and cellular supernatants were assessed by using an enzyme-linked immunosorbent assay kit. The results demonstrated that, compared to the HA strain, the aCD11c-HA strain significantly increased the activation of BMDCs and increased the production of CD4+ gamma interferon-positive (IFN-γ+) T cells, CD8+ IFN-γ+ T cells, and IFN-γ in the cell culture supernatant in vitro Consistent with these results, the aCD11c-HA strain clearly increased the activation and maturation of DCs, the HA-specific responses of CD4+ IFN-γ+ T cells, CD8+ IFN-γ+ T cells, and CD8+ CD107a+ T cells, and the proliferation of T cells in the spleen, finally increasing the levels of specific antibodies and neutralizing antibodies in mice. In addition, the protection of immunized mice was observed after viral infection, as evidenced by improved weight loss, survival, and lung pathology. The adoptive transfer of CD8+ T cells from the aCD11c-HA mice to NOD/Lt-SCID mice resulted in a certain level of protection after influenza virus infection, highlighting the efficacy of the aCD11c targeting strategy.


Asunto(s)
Antígeno CD11c/inmunología , Células Dendríticas/inmunología , Inmunidad Celular/inmunología , Lactobacillus plantarum/inmunología , Anticuerpos de Cadena Única/inmunología , Animales , Anticuerpos Neutralizantes/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/virología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/virología , Células Dendríticas/virología , Femenino , Subtipo H1N1 del Virus de la Influenza A/inmunología , Interferón gamma/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones SCID , Infecciones por Orthomyxoviridae/inmunología , Infecciones por Orthomyxoviridae/virología
11.
Scand J Immunol ; 91(3): e12838, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31630413

RESUMEN

To evaluate the levels of recent thymic emigrant (RTE) CD4+ T cells in HIV-infected children and to explore the associations among their frequency, antiretroviral treatment (ART) adherence, and CD4+ T cell restoration. The group evaluated comprised 85 HIV-infected patients classified as subjects with moderate or severe immunosuppression or as those with no evidence of immunosuppression. To evaluate the association between the frequency of RTE CD4+ T cells and ART adherence, 23 of the 85 patients were evaluated at two different time points during a one-year follow-up period. Children with severe immunosuppression had lower frequencies of RTE CD4+ T cells compared with children without evidence of immunosuppression (P < .001). The frequency of RTE CD4+ T cells in children with a high rate of adherence was significantly higher (P < .05) than that observed among those with suboptimal adherence. The latter group presented with infectious intercurrences on admission that decreased after initiation of treatment along with improved CD4+ and RTE naïve CD4+ T cells counts. The adequate ART adherence is essential for immune reconstitution, which might be reflected by the levels of RTE CD4+ T cells.


Asunto(s)
Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos/inmunología , Infecciones por VIH/inmunología , VIH-1/inmunología , Timocitos/inmunología , Adolescente , Terapia Antirretroviral Altamente Activa , Biomarcadores , Linfocitos T CD4-Positivos/metabolismo , Movimiento Celular , Niño , Preescolar , Femenino , Infecciones por VIH/tratamiento farmacológico , Humanos , Inmunofenotipificación , Lactante , Masculino , Cumplimiento de la Medicación , Timocitos/metabolismo , Resultado del Tratamiento , Carga Viral
12.
Scand J Immunol ; 91(2): e12836, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31598989

RESUMEN

PD-1/PD-L1 pathway is crucial to immune regulation by controlling the balance between T cell tolerance and activation. However, the association between PD-1/PD-L1 pathway and regulatory B cells has not been fully investigated in allergic rhinitis. In this study, we detected the number of peripheral CD19+ CD25+ Bregs and the expression of IL-10 on this cell subset in healthy control and patients with allergic rhinitis using flow cytometry. Then, we evaluated the level of PD-L1 in CD19+ CD25+ Bregs and investigated the correlation between PD-L1 and CD4+ follicular T helper cells. Finally, we studied the effects of anti-PD-L1 on the apoptosis of Bregs and the production of IL-10. Comparing with healthy controls, the percentage of CD19+ CD25+ Bregs and the expression of IL-10 were both significantly decreased in AR group. In addition, the expression of PD-L1 on CD19+ CD25+ Bregs was also lower in allergic rhinitis patients. Interestingly, a negative correlation was found between the expression of PD-L1+ Bregs and CD4+ CXCR5+ follicular T helper cells. In vitro assay revealed that anti-PD-L1 promoted Bregs apoptosis and inhibited the expression of IL-10 in CD19+ CD25+ Bregs. Collectively, these results suggest that PD-L1 expressed on CD19+ CD25+ Bregs may be a potential regulator in the treatment of allergic rhinitis. Blockade of PD-1/PD-L1 pathway might be a valuable pathogenic target for allergic rhinitis through inhibiting the secretion of immunosuppressive cytokine and promoting CD19+ CD25+ Bregs apoptosis.


Asunto(s)
Linfocitos B Reguladores/inmunología , Antígeno B7-H1/metabolismo , Linfocitos T CD4-Positivos/inmunología , Centro Germinal/inmunología , Interleucina-10/sangre , Receptor de Muerte Celular Programada 1/metabolismo , Rinitis Alérgica/inmunología , Adulto , Antígenos CD19/metabolismo , Apoptosis , Femenino , Humanos , Tolerancia Inmunológica , Subunidad alfa del Receptor de Interleucina-2 , Masculino , Persona de Mediana Edad , Transducción de Señal
13.
Arch Virol ; 165(2): 321-330, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31828511

RESUMEN

Persistence of human immunodeficiency virus 1 (HIV-1) latency and residual immune activation remain major barriers to treatment in patients receiving highly active antiretroviral therapy (HAART). In the present study, we investigated the molecular mechanisms of persistent HIV infection and residual immune activation in HAART-treated patients. We showed that the expression level of B-cell CLL/lymphoma 11B (BCL11B) was significantly increased in CD4+T cells from HIV-infected patients undergoing HAART, and this was accompanied by increased expression of BCL11B-associated chromatin modifiers and inflammatory factors in comparison to healthy controls and untreated patients with HIV. In vitro assays showed that BCL11B significantly inhibited HIV-1 long terminal repeat (LTR)-mediated transcription. Knockdown of BCL11B resulted in the activation of HIV latent cells, and dissociation of BCL11B and its related chromatin remodeling factors from the HIV LTR. Our findings suggested that increased expression of BCL11B and its related chromatin modifiers contribute to HIV-1 transcriptional silencing, and alteration of BCL11B levels might lead to abnormal transcription and inflammation.


Asunto(s)
Ensamble y Desensamble de Cromatina/genética , Infecciones por VIH/genética , VIH-1/genética , Proteínas Represoras/genética , Proteínas Represoras/inmunología , Transcripción Genética/inmunología , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/inmunología , Adulto , Terapia Antirretroviral Altamente Activa/métodos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/virología , Cromatina/genética , Cromatina/virología , Ensamble y Desensamble de Cromatina/efectos de los fármacos , Ensamble y Desensamble de Cromatina/inmunología , Femenino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Duplicado del Terminal Largo de VIH/genética , Duplicado del Terminal Largo de VIH/inmunología , VIH-1/efectos de los fármacos , VIH-1/inmunología , Humanos , Masculino , Transcripción Genética/efectos de los fármacos , Latencia del Virus/genética , Latencia del Virus/inmunología
14.
Parasitol Int ; 74: 101994, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31634628

RESUMEN

IL-27, a regulatory cytokine, plays critical roles in the prevention of immunopathology during Plasmodium infection. We examined these roles in the immune responses against Plasmodium chabaudi infection using the Il-27ra-/- mice. While IL-27 was expressed at high levels during the early phase of the infection, enhanced CD4+ T cell function and reduction in parasitemia were observed mainly during the chronic phase in the mutant mice. In mice infected with P. chabaudi and cured with drug, CD4+ T cells in the Il-27ra-/- mice exhibited enhanced CD4+ T-cell responses, indicating the inhibitory role of IL-27 on the protective immune responses. To determine the role of IL-27 in detail, we performed CD4+ T-cell transfer experiments. The Il-27ra-/- and Il27p28-/- mice were first infected with P. chabaudi and then cured using drug treatment. Plasmodium-antigen primed CD4+ T cells were prepared from these mice and transferred into the recipient mice, followed by infection with the heterologous parasite P. berghei ANKA. Il-27ra-/- CD4+ T cells in the infected recipient mice did not produce IL-10, indicating that IL-10 production by primed CD4+ T cells is IL-27 dependent. Il27p28-/- CD4+ T cells that were primed in the absence of IL-27 exhibited enhanced recall responses during the challenge infection with P. berghei ANKA, implying that IL-27 receptor signaling during the primary infection affects recall responses in the long-term via the regulation of the memory CD4+ T cell generation. These features highlighted direct and time-transcending roles of IL-27 in the regulation of immune responses against chronic infection with Plasmodium parasites.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Regulación de la Expresión Génica/inmunología , Memoria Inmunológica , Interleucina-10/inmunología , Interleucina-27/genética , Malaria/inmunología , Animales , Enfermedad Crónica , Interleucina-27/inmunología , Malaria/tratamiento farmacológico , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Plasmodium chabaudi
15.
Immunity ; 51(6): 1074-1087.e9, 2019 12 17.
Artículo en Inglés | MEDLINE | ID: mdl-31784108

RESUMEN

Infections induce complex host responses linked to antiviral defense, inflammation, and tissue damage and repair. We hypothesized that the liver, as a central metabolic hub, may orchestrate systemic metabolic changes during infection. We infected mice with chronic lymphocytic choriomeningitis virus (LCMV), performed RNA sequencing and proteomics of liver tissue, and integrated these data with serum metabolomics at different infection phases. Widespread reprogramming of liver metabolism occurred early after infection, correlating with type I interferon (IFN-I) responses. Viral infection induced metabolic alterations of the liver that depended on the interferon alpha/beta receptor (IFNAR1). Hepatocyte-intrinsic IFNAR1 repressed the transcription of metabolic genes, including Otc and Ass1, which encode urea cycle enzymes. This led to decreased arginine and increased ornithine concentrations in the circulation, resulting in suppressed virus-specific CD8+ T cell responses and ameliorated liver pathology. These findings establish IFN-I-induced modulation of hepatic metabolism and the urea cycle as an endogenous mechanism of immunoregulation. VIDEO ABSTRACT.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Interferón Tipo I/inmunología , Hígado/metabolismo , Virus de la Coriomeningitis Linfocítica/inmunología , Receptor de Interferón alfa y beta/metabolismo , Animales , Arginina/sangre , Línea Celular , Cricetinae , Femenino , Hepatocitos/metabolismo , Hígado/inmunología , Hígado/virología , Coriomeningitis Linfocítica/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ornitina/sangre , Ornitina Carbamoiltransferasa/genética , Transducción de Señal/inmunología , Urea/metabolismo , Células Vero
16.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(11): 1008-1013, 2019 Nov.
Artículo en Chino | MEDLINE | ID: mdl-31878997

RESUMEN

Objective To explore the role of extracellular secretory protein sulfatase-1 (SULF1) in colon cancer prognosis and immune cell infiltration. Methods SULF1 gene expression level in tumor and normal tissues was identified via Oncomine database and Tumor Immune Estimation Resource (Timer) site. The correlation between SULF1 gene expression level and colon cancer prognosis was obtained by Prognoscan database and Gene Expression Profiling Interactive Analysis (GEPIA). The relationship for SULF1 geneexpression level in colon cancer immune cell infiltration and tumor-associated macrophage surface markers was retrieved by Timer database gene module and gene correlation module. The results were further verified by GEPIA database. Results The results of Timer and Oncomine database analysis indicated that SULF1 was highly expressed in colon cancer. The results of Prognoscan chip GSE17536 and GEPIA database showed that the high expression of SULF1 was positively correlated with the poor prognosis of colon cancer. SULF1 was positively correlated with the infiltration of colon cancer immune cells CD8+ T cells, CD4+ T cells, macrophages, neutrophils and dendritic cells, and not associated with B cells. SULF1 had the strongest positive correlation with macrophages (r=0.628), and the correlation with M2-type macrophages was significantly higher than that with M1-type macrophages. Conclusion SULF1 is highly expressed and positively correlated with poor prognosis in colon cancer. The tumor-associated macrophage infiltration may be one of involved mechanisms.


Asunto(s)
Neoplasias del Colon/metabolismo , Sulfotransferasas/metabolismo , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Neoplasias del Colon/diagnóstico , Perfilación de la Expresión Génica , Humanos , Macrófagos/inmunología , Pronóstico
17.
PLoS One ; 14(12): e0225415, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31869342

RESUMEN

A significant proportion of HIV-infected patients experiencing a late diagnosis highlights the need to define immunological protocols able to help the clinicians in identifying patients at higher risk for immunological failure. The aim of the study was to evaluate the feasibility of easy cytometric tests in defining the effect of antiretroviral treatment (cART) on immunological homeostasis and in identifying predictive markers of early immune recovery. Chronic HIV infected patients (n = 202) were enrolled in a prospective multicentric study, and their immunological profile was studied before (w0) and after 24 weeks (w24) of antiretroviral treatment (cART) using a standardized flow cytometric panel. Based on CD4 T cell count before treatment, patients were divided in late (LP: CD4 <350/mmc), intermediate (IP: 350/mmc500/mmc) presenters. In all groups, cART introduction increased CD4 and CD4/CD8 T cell ratio, naïve T cell (CD4 and CD8) and CD127-expressing CD4 T cells. In parallel, cART significantly reduced effector memory T cells (CD4 and CD8) and T cell activation (CD38+CD8 and CD95+CD4 T cells). Moreover, the frequency of Naïve and Effector CD4 T cells before treatment correlated with several immune parameters key associated with the pathogenesis of HIV, thus mirroring the health of immune system. Interestingly, we identified the Naïve/Effector CD4 T cell ratio (N/EM) at w0 as a marker able to predict early immune recovery. Specifically, in LP, N/EM ratio was significantly higher in immunological responder patients (CD4>500/mmc at w24) when compared to immunological non responder (CD4 T cells <500/mmc at w24). Finally, a multivariate analysis indicates that after 24w patients with N/EM ratio higher than 1.86 at w0 recovered 96 CD4 T cells more than those with N/EM ratio lower than 0.46. Altogether, our data define an easy protocol able to define reliable immunological markers useful for the characterization of immune profile in viremic HIV patients and identify the naïve/effector CD4 T cell ratio as a new tool able to predict an early immune reconstitution potential.


Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Linfocitos T CD4-Positivos/inmunología , Infecciones por VIH/inmunología , Reconstitución Inmune , Adulto , Terapia Antirretroviral Altamente Activa , Recuento de Linfocito CD4 , Femenino , Infecciones por VIH/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Resultado del Tratamiento
18.
PLoS Comput Biol ; 15(11): e1007401, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31693657

RESUMEN

The novel therapies with immune checkpoint inhibitors hold great promises for patients with chronic virus infections and cancers. This is based mainly on the partial reversal of the exhausted phenotype of antigen-specific cytotoxic CD8 T cells (CTL). Recently, we have shown that the restoration of HIV-specific T cell function depends on the HIV infection stage of an infected individual. Here we aimed to answer two fundamental questions: (i) Can one estimate growth parameters for the HIV-specific proliferative responsiveness upon PD-L1 blockade ex vivo? (ii) Can one use these parameter estimates to predict clinical benefit for HIV-infected individuals displaying diverse infection phenotypes? To answer these questions, we first analyzed HIV-1 Gag-specific CD8 T cell proliferation by time-resolved CFSE assays and estimated the effect of PD-L1 blockade on division and death rates, and specific precursor frequencies. These values were then incorporated into a model for CTL-mediated HIV control and the effects on CTL frequencies, viral loads and CD4 T cell counts were predicted for different infection phenotypes. The biggest absolute increase in CD4 T cell counts was in the group of slow progressors while the strongest reduction in virus loads was observed in progressor patients. These results suggest a significant clinical benefit only for a subgroup of HIV-infected individuals. However, as PD1 is a marker of lymphocyte activation and expressed on several lymphocyte subsets including also CD4 T cells and B cells, we subsequently examined the multiple effects of anti-PD-L1 blockade beyond those on CD8 T cells. This extended model then predicts that the net effect on HIV load and CD4 T cell number depends on the interplay between positive and negative effects of lymphocyte subset activation. For a physiologically relevant range of affected model parameters, PD-L1 blockade is likely to be overall beneficial for HIV-infected individuals.


Asunto(s)
Antígeno B7-H1/metabolismo , Linfocitos T CD8-positivos/inmunología , Infecciones por VIH/terapia , Apoptosis , Antígeno B7-H1/fisiología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/fisiología , División Celular , Proliferación Celular , Infecciones por VIH/inmunología , VIH-1/inmunología , Humanos , Activación de Linfocitos/inmunología , Modelos Teóricos , Linfocitos T Citotóxicos/inmunología , Carga Viral
19.
Mol Immunol ; 116: 167-173, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31698163

RESUMEN

Primary biliary cholangitis (PBC) is considered as a model of organ-specific autoimmune disease based on the serological findings of anti-mitochondrial antibodies (AMA), infiltrates of T cells, and selective destruction of epithelial cells in the liver. T-cell-mediated autoimmune mechanisms are considered to be involved in the pathogenesis of primary biliary cholangitis (PBC). In this context, we used a combination of multiplex-PCR, Illumina sequencing and IMGT/HighV-QUEST for a standardized analysis of the T cell receptor ß-chain (TCRß) repertoire of CD4+naive T cells in PBC patients compared with healthy volunteers. Nonfunctional TCRs were used to study the pre-selection TCR repertoire, as they are not subject to functional selection (positive and negative selection). Functional TCRs were used to study the post-selection TCR repertoire. The results showed that there was not significant difference between PBC patients and healthy volunteers in TCRß diversity, CDR3 length distributions, degree of sequence sharing, and usage frequency of TRBV and TRBJ segments, no matter in Pre-selection or Post-selection repertoires. In conclusion, early events in thymic T cell development and repertoire generation are not abnormality in PBC patients. The breakdown of self-tolerance to autoantigen may be derived from other immunological dysregulation or environmental agents.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Cirrosis Hepática Biliar/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Adulto , Anciano , Autoantígenos/inmunología , Enfermedades Autoinmunes/inmunología , Células Epiteliales/inmunología , Femenino , Voluntarios Sanos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Hígado/inmunología , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa Multiplex/métodos
20.
Anticancer Res ; 39(11): 5911-5918, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31704815

RESUMEN

BACKGROUND/AIM: Double-negative T (DNT) cells are phenotypically CD3+CD4-CD8-T cells. This study aimed to investigate the anti-cancer activity of DNT cells against pancreatic cancer cells. MATERIALS AND METHODS: DNT cells were isolated from human peripheral blood. The effect of DNT cells on proliferation and invasion of the human pancreatic cell line Panc-1 was assessed. Expression of Nrf2 and Fas in Panc-1 cells co-cultured with DNT cells was analyzed with RT-PCR. The supernatants of Panc-1 and DNT co-cultures were analyzed with ELISA for IFN-r and FasL levels. RESULTS: The isolated DNT cell phenotype was CD4-CD8-CD56- CD3+TCR (T cell receptor) α/ß+ T cells with more than 90% purity. Panc-1 cell proliferation was significantly inhibited by co-culture with DNT cells. Panc-1 cells co-cultured with DNT cells showed significantly reduced cell invasion. Panc-1 cells co-cultured with DNT cells showed increased Nrf2 and Fas mRNA expression. Increased INF-r and FasL levels were detected in the supernatants of co-cultures of DNT and pancreatic cells. CONCLUSION: DNT cells inhibited proliferation and invasion of human pancreatic cancer cells. The INF-r, Fas/FasL pathway and Nrf2 may be involved in the anti-cancer effect of DNT cells against human pancreatic cancer.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Técnicas de Cocultivo/métodos , Activación de Linfocitos/inmunología , Neoplasias Pancreáticas/prevención & control , Apoptosis , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/metabolismo , Proliferación Celular , Proteína Ligando Fas/metabolismo , Humanos , Factor 2 Relacionado con NF-E2/metabolismo , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Receptores de Interferón/metabolismo , Células Tumorales Cultivadas , Receptor fas/metabolismo
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