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1.
Rheumatology (Oxford) ; 60(12): 5595-5600, 2021 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-33590850

RESUMEN

OBJECTIVES: We sought to clarify the presence of radiographic thymus variants using a scoring system, and their association with clinical and immunological features in RA patients. METHODS: A total of 387 RA patients were randomly selected from all patients visiting our department who underwent chest CT scanning, with exclusion of patients with thymoma or thymic cyst, or age < 30 years. Thymus size and attenuation score in axial CT images were quantitatively interpreted and assessed. Associations between immunophenotype data and clinical and serological features were analysed in a subset of patients. RESULTS: Thymic enlargement was found in 76 (19.6%) patients, and a thymus attenuation score ≥ 2 was found in 50 (12.9%) patients. The score was significantly associated with antibodies to ACPA positivity. Thymic enlargement was significantly associated with the proportions of CD4+ effector memory T cells. CONCLUSION: Radiographic thymus variants were frequently observed in RA patients and may reflect an abnormal immune response involved in the pathogenesis of RA.


Asunto(s)
Artritis Reumatoide/diagnóstico , Autoanticuerpos/sangre , Células T de Memoria/inmunología , Timoma/diagnóstico , Timo/diagnóstico por imagen , Neoplasias del Timo/diagnóstico , Tomografía Computarizada por Rayos X/métodos , Anciano , Artritis Reumatoide/sangre , Artritis Reumatoide/complicaciones , Autoanticuerpos/inmunología , Estudios Transversales , Femenino , Citometría de Flujo , Estudios de Seguimiento , Humanos , Inmunidad Celular , Inmunofenotipificación , Masculino , Células T de Memoria/patología , Persona de Mediana Edad , Estudios Retrospectivos , Timoma/complicaciones , Timoma/inmunología , Neoplasias del Timo/complicaciones , Neoplasias del Timo/inmunología
2.
Ann Rheum Dis ; 78(10): 1346-1356, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31167762

RESUMEN

OBJECTIVES: Rheumatoid arthritis (RA) is an autoimmune disease accompanied by lymphocyte infiltration into joint synovium. While T cells are considered to be important for its pathogenesis, the features that are the most relevant to disease and how they change after treatment remain unclear. The aim of this study was to clarify the characteristics of T cells in RA, comprehensively. METHODS: We enrolled a total of 311 patients with RA and 73 healthy participants, and carefully classified them by disease state, constructed multiple cohorts and analysed clinical samples from them in a stepwise manner. We performed immunophenotyping with multiple evaluation axes, and two independent transcriptome analyses complementary to each other. RESULTS: We identified that 'effector memory-Tfh' subset was specifically expanded in the peripheral blood (PB) of patients with RA in correlation with disease activity, and reverted after treatment. Besides, we revealed distinct features of T cells in synovial fluid (SF) that the expression of Tfh/Tph-related genes and pro-inflammatory cytokines and chemokines, including CXCL13, were significantly enriched, whereas these phenotype were Th1-like. Finally, we identified specific pathways, such as mTORC1, IL-2-stat5, E2F, cell cycle and interferon-related genes, that were significantly enriched in SF, in particular, as well as PB of untreated patients with RA, and notably, these features reverted after treatment. CONCLUSION: Our multi-dimensional investigation identified disease relevant T-cell subsets and gene signatures deeply involved in pathogenesis of RA. These findings could aid in our understanding of essential roles of T cells in RA and will facilitate to development better diagnostic and therapeutic interventions.


Asunto(s)
Artritis Reumatoide/inmunología , Transducción de Señal/inmunología , Subgrupos de Linfocitos T/inmunología , Adulto , Artritis Reumatoide/genética , Quimiocina CXCL13/inmunología , Citocinas/inmunología , Femenino , Humanos , Inmunofenotipificación , Masculino , Persona de Mediana Edad , Líquido Sinovial/inmunología
3.
Immunity ; 30(3): 372-83, 2009 Mar 20.
Artículo en Inglés | MEDLINE | ID: mdl-19285436

RESUMEN

Intracellular cyclic adenosine monophosphate (cAMP) suppresses innate immunity by inhibiting proinflammatory cytokine production from monocytic cells. Enhanced expression of interleukin-10 (IL-10) has been suggested to be the mechanism of suppression. However, cAMP is still capable of suppressing production of the cytokines TNF-alpha and IL-12 in IL-10-deficient dendritic cells (DCs). Here, we demonstrated that the transcription factor c-Fos was responsible for the cAMP-mediated suppression of inflammatory cytokine production. c-Fos accumulated at high amounts in response to cAMP and lipopolysaccharide (LPS). Overexpression of c-Fos suppressed LPS-induced cytokine production, whereas cAMP-mediated suppression of TNF-alpha and IL-12 was impaired in Fos(-/-) DCs or in RAW264.7 cells treated with c-Fos siRNA. c-Fos physically interacted with p65 protein and reduced the recruitment of p65 to the Tnf promoter. Multiple sites of c-Fos were phosphorylated by the IKKbeta protein. Thus, we propose that c-Fos is a substrate of IKKbeta and is responsible for the immunosuppressive effect of cAMP.


Asunto(s)
AMP Cíclico/inmunología , Citocinas/metabolismo , Regulación de la Expresión Génica , Proteínas Proto-Oncogénicas c-fos/inmunología , Animales , Células Cultivadas , Citocinas/antagonistas & inhibidores , Células Dendríticas/inmunología , Ensayo de Inmunoadsorción Enzimática , Quinasa I-kappa B/metabolismo , Inmunidad Innata , Ratones , Ratones Noqueados , Fosforilación , Proteínas Proto-Oncogénicas c-fos/clasificación , Proteínas Proto-Oncogénicas c-fos/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
4.
Bioorg Med Chem ; 26(3): 721-736, 2018 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-29342416

RESUMEN

Novel small molecules were synthesized and evaluated as retinoic acid receptor-related orphan receptor-gamma t (RORγt) inverse agonists for the treatment of inflammatory and autoimmune diseases. A hit compound, 1, was discovered by high-throughput screening of our compound library. The structure-activity relationship (SAR) study of compound 1 showed that the introduction of a chlorine group at the 3-position of 4-cyanophenyl moiety increased the potency and a 3-methylpentane-1,5-diamide linker is favorable for the activity. The carbazole moiety of 1 was also optimized; a quinazolinedione derivative 18i suppressed the increase of IL-17A mRNA level in the lymph node of a rat model of experimental autoimmune encephalomyelitis (EAE) upon oral administration. These results indicate that the novel quinazolinedione derivatives have great potential as orally available small-molecule RORγt inverse agonists for the treatment of Th17-driven autoimmune diseases. A U-shaped bioactive conformation of this chemotype with RORγt protein was also observed.


Asunto(s)
Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/agonistas , Quinazolinonas/química , Administración Oral , Animales , Sitios de Unión , Agonismo Inverso de Drogas , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/patología , Encefalomielitis Autoinmune Experimental/veterinaria , Femenino , Humanos , Concentración 50 Inhibidora , Interleucina-17/genética , Interleucina-17/metabolismo , Células Jurkat , Simulación del Acoplamiento Molecular , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Unión Proteica/efectos de los fármacos , Estructura Terciaria de Proteína , Quinazolinonas/administración & dosificación , Quinazolinonas/metabolismo , Quinazolinonas/farmacología , Ratas , Ratas Endogámicas Lew , Solubilidad , Relación Estructura-Actividad , Células Th17/citología , Células Th17/efectos de los fármacos , Células Th17/metabolismo
5.
Bioorg Med Chem ; 26(2): 483-500, 2018 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-29262987

RESUMEN

A series of novel phenylglycinamides as retinoic acid receptor-related orphan receptor-gamma t (RORγt) inverse agonists were discovered through optimization of a high-throughput screen hit 1. (R)-N-(2-((3,5-Difluoro-4-(trimethylsilyl)phenyl) amino)-1-(4-methoxyphenyl)-2-oxoethyl)-3-hydroxy-N-methylisoxazole-5-carboxamide (22) was identified as one of the best of these compounds. It displayed higher subtype selectivity and specificity over other nuclear receptors and demonstrated in vivo potency to suppress the transcriptional activity of RORγt in a mouse PD (pharmacodynamic) model upon oral administration.


Asunto(s)
Descubrimiento de Drogas , Glicina/análogos & derivados , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/agonistas , Administración Oral , Animales , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Glicina/administración & dosificación , Glicina/química , Glicina/farmacología , Humanos , Células Jurkat , Masculino , Ratones , Ratones Endogámicos BALB C , Modelos Animales , Modelos Moleculares , Estructura Molecular , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Relación Estructura-Actividad
6.
Cell Stem Cell ; 31(6): 795-802.e6, 2024 Jun 06.
Artículo en Inglés | MEDLINE | ID: mdl-38848686

RESUMEN

CD4+ T cells induced from human iPSCs (iCD4+ T cells) offer a therapeutic opportunity for overcoming immune pathologies arising from hematopoietic stem cell transplantation. However, most iCD4+ T cells are conventional helper T cells, which secrete inflammatory cytokines. We induced high-level expression of FOXP3, a master transcription factor of regulatory T cells, in iCD4+ T cells. Human iPSC-derived, FOXP3-induced CD4+ T (iCD4+ Treg-like) cells did not secrete inflammatory cytokines upon activation. Moreover, they showed demethylation of the Treg-specific demethylation region, suggesting successful conversion to immunosuppressive iCD4+ Treg-like cells. We further assessed these iCD4+ Treg-like cells for CAR-mediated immunosuppressive ability. HLA-A2 CAR-transduced iCD4+ Treg-like cells inhibited CD8+ cytotoxic T cell (CTL) division in a mixed lymphocyte reaction assay with A2+ allogeneic CTLs and suppressed xenogeneic graft-versus-host disease (GVHD) in NSG mice treated with A2+ human PBMCs. In most cases, these cells suppressed the xenogeneic GvHD progression as much as natural CD25+CD127- Tregs did.


Asunto(s)
Enfermedad Injerto contra Huésped , Células Madre Pluripotentes Inducidas , Receptores Quiméricos de Antígenos , Linfocitos T Reguladores , Humanos , Enfermedad Injerto contra Huésped/inmunología , Animales , Linfocitos T Reguladores/inmunología , Células Madre Pluripotentes Inducidas/metabolismo , Receptores Quiméricos de Antígenos/metabolismo , Receptores Quiméricos de Antígenos/inmunología , Ratones , Factores de Transcripción Forkhead/metabolismo , Xenoinjertos , Ratones Endogámicos NOD , Modelos Animales de Enfermedad , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo
7.
Commun Biol ; 6(1): 500, 2023 05 09.
Artículo en Inglés | MEDLINE | ID: mdl-37161050

RESUMEN

T cells play important roles in autoimmune diseases, but it remains unclear how to optimally manipulate them. We focused on the T cell immunoreceptor with Ig and ITIM domains (TIGIT), a coinhibitory molecule that regulates and is expressed in T cells. In autoimmune diseases, the association between TIGIT-expressing cells and pathogenesis and the function of human-TIGIT (hu-TIGIT) signalling modification have not been fully elucidated. Here we generated anti-hu-TIGIT agonistic monoclonal antibodies (mAbs) and generated hu-TIGIT knock-in mice to accurately evaluate the efficacy of mAb function. Our mAb suppressed the activation of CD4+ T cells, especially follicular helper T and peripheral helper T cells that highly expressed TIGIT, and enhanced the suppressive function of naïve regulatory T cells. These results indicate that our mAb has advantages in restoring the imbalance of T cells that are activated in autoimmune diseases and suggest potential clinical applications for anti-hu-TIGIT agonistic mAbs as therapeutic agents.


Asunto(s)
Enfermedades Autoinmunes , Linfocitos T Reguladores , Animales , Ratones , Enfermedades Autoinmunes/tratamiento farmacológico , Transducción de Señal , Anticuerpos Monoclonales/farmacología , Receptores Inmunológicos/genética
8.
J Exp Med ; 203(4): 1021-31, 2006 Apr 17.
Artículo en Inglés | MEDLINE | ID: mdl-16606674

RESUMEN

Suppressor of cytokine signaling (SOCS)3 is a major negative feedback regulator of signal transducer and activator of transcription (STAT)3-activating cytokines. Transgenic mouse studies indicate that high levels of SOCS3 in T cells result in type 2 T helper cell (Th2) skewing and lead to hypersensitivity to allergic diseases. To define the physiological roles of SOCS3 in T cells, we generated T cell-specific SOCS3 conditional knockout mice. We found that the mice lacking SOCS3 in T cells showed reduced immune responses not only to ovalbumin-induced airway hyperresponsiveness but also to Leishmania major infection. In vitro, SOCS3-deficient CD4+ T cells produced more transforming growth factor (TGF)-beta1 and interleukin (IL)-10, but less IL-4 than control T cells, suggesting preferential Th3-like differentiation. We found that STAT3 positively regulates TGF-beta1 promoter activity depending on the potential STAT3 binding sites. Furthermore, chromatin immunoprecipitation assay revealed that more STAT3 was recruited to the TGF-beta1 promoter in SOCS3-deficient T cells than in control T cells. The activated STAT3 enhanced TGF-beta1 and IL-10 expression in T cells, whereas the dominant-negative form of STAT3 suppressed these. From these findings, we propose that SOCS3 regulates the production of the immunoregulatory cytokines TGF-beta1 and IL-10 through modulating STAT3 activation.


Asunto(s)
Regulación hacia Abajo/inmunología , Interleucina-10/biosíntesis , Proteínas Supresoras de la Señalización de Citocinas/deficiencia , Proteínas Supresoras de la Señalización de Citocinas/genética , Linfocitos T Colaboradores-Inductores/metabolismo , Factor de Crecimiento Transformador beta/biosíntesis , Animales , Diferenciación Celular/inmunología , Leishmania major/inmunología , Leishmaniasis Cutánea/genética , Leishmaniasis Cutánea/inmunología , Leishmaniasis Cutánea/metabolismo , Ratones , Ratones Noqueados , Regiones Promotoras Genéticas , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/fisiología , Proteína 3 Supresora de la Señalización de Citocinas , Proteínas Supresoras de la Señalización de Citocinas/fisiología , Linfocitos T Colaboradores-Inductores/citología , Linfocitos T Colaboradores-Inductores/inmunología , Células Th2/inmunología , Células Th2/metabolismo , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta1 , Regulación hacia Arriba/genética , Regulación hacia Arriba/inmunología
9.
J Exp Med ; 203(6): 1391-7, 2006 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-16717119

RESUMEN

Approximately 20% of human cancers are estimated to develop from chronic inflammation. Recently, the NF-kappaB pathway was shown to play an essential role in promoting inflammation-associated cancer, but the role of the JAK/STAT pathway, another important signaling pathway of proinflammatory cytokines, remains to be investigated. Suppressor of cytokine signaling-1 (SOCS1) acts as an important physiological regulator of cytokine responses, and silencing of the SOCS1 gene by DNA methylation has been found in several human cancers. Here, we demonstrated that SOCS1-deficient mice (SOCS1-/- Tg mice), in which SOCS1 expression was restored in T and B cells on a SOCS1-/- background, spontaneously developed colorectal carcinomas carrying nuclear beta-catenin accumulation and p53 mutations at 6 months of age. However, interferon (IFN)gamma-/- SOCS1-/- mice and SOCS1-/- Tg mice treated with anti-IFNgamma antibody did not develop such tumors. STAT3 and NF-kappaB activation was evident in SOCS1-/- Tg mice, but these were not sufficient for tumor development because these are also activated in IFNgamma-/- SOCS1-/- mice. However, colons of SOCS1-/- Tg mice, but not IFNgamma-/- SOCS1-/- mice, showed hyperactivation of STAT1, which resulted in the induction of carcinogenesis-related enzymes, cyclooxygenase-2 and inducible nitric oxide synthase. These data strongly suggest that SOCS1 is a unique antioncogene which prevents chronic inflammation-mediated carcinogenesis by regulation of the IFNgamma/STAT1 pathways.


Asunto(s)
Neoplasias del Colon/inmunología , Neoplasias Colorrectales/inmunología , Interferón gamma/toxicidad , Factor de Transcripción STAT1/metabolismo , Proteínas Supresoras de la Señalización de Citocinas/deficiencia , Animales , Proteínas Portadoras/genética , Neoplasias del Colon/genética , Neoplasias Colorrectales/genética , Interferón gamma/deficiencia , Interferón gamma/genética , Ratones , Ratones Noqueados , FN-kappa B/metabolismo , Proteínas Recombinantes/metabolismo , Proteínas Represoras/genética , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Proteína 1 Supresora de la Señalización de Citocinas , Proteínas Supresoras de la Señalización de Citocinas/genética
10.
Sci Rep ; 11(1): 16691, 2021 08 17.
Artículo en Inglés | MEDLINE | ID: mdl-34404865

RESUMEN

While numerous disease-modifying anti-rheumatic drugs (DMARDs) have brought about a dramatic paradigm shift in the management of rheumatoid arthritis (RA), unmet needs remain, such as the small proportion of patients who achieve drug-free status. The aim of this study was to explore key molecules for remission at the T cell level, which are known to be deeply involved in RA pathogenesis, and investigate the disease course of patients who achieved molecular remission (MR). We enrolled a total of 46 patients with RA and 10 healthy controls (HCs). We performed gene expression profiling and selected remission signature genes in CD4+ T cells and CD8+ T cells from patients with RA using machine learning methods. In addition, we investigated the benefits of achieving MR on disease control. We identified 9 and 23 genes that were associated with clinical remission in CD4+ and CD8+ T cells, respectively. Principal component analysis (PCA) demonstrated that their expression profiling was similar to those in HCs. For the remission signature genes in CD4+ T cells, the PCA result was reproduced using a validation cohort, indicating the robustness of these genes. A trend toward better disease control was observed during 12 months of follow-up in patients treated with tocilizumab in deep MR compared with those in non-deep MR, although the difference was not significant. The current study will promote our understanding of the molecular mechanisms necessary to achieve deep remission during the management of RA.


Asunto(s)
Artritis Reumatoide/genética , Transcriptoma , Artritis Reumatoide/terapia , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/metabolismo , Estudios Transversales , Humanos , Aprendizaje Automático , Inducción de Remisión
11.
Inflamm Regen ; 40: 23, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33014207

RESUMEN

In 2007, Human-induced pluripotent stem cells (iPSCs) were generated by transducing four genes (Oct3/4, Sox2, Klf4, c-Myc). Because iPSCs can differentiate into any types of cells in the body and have fewer ethical issues compared to embryonic stem (ES) cells, application of iPSCs for regenerative medicine has been actively examined. In fact, iPSCs have already been used for clinical applications, but at present, only autologous iPSC-derived grafts or HLA homozygous iPSC-derived grafts are being transplanted into patients following HLA matching. HLA is an important molecule that enables the immune system differentiates between self and non-self-components; thus, HLA mismatch is a major hurdle in the transplantation of iPSCs. To deliver inexpensive off-the-shelf iPSC-derived regenerative medicine products to more patients, it is necessary to generate universal iPSCs that can be transplanted regardless of the HLA haplotypes. The current strategy to generate universal iPSCs has two broad aims: deleting HLA expression and avoiding attacks from NK cells, which are caused by HLA deletion. Deletion of B2M and CIITA genes using the CRISPR/Cas9 system has been reported to suppress the expression of HLA class I and class II, respectively. Transduction of NK inhibitory ligands, such as HLA-E and CD47, has been used to avoid NK cell attacks. Most recently, the HLA-C retaining method has been used to generate semi-universal iPSCs. Twelve haplotypes of HLA-C retaining iPSCs can cover 95% of the global population. In future, studying which types of universal iPSCs are most effective for engraftment in various physiological conditions is necessary.

12.
Nat Commun ; 8: 15338, 2017 05 22.
Artículo en Inglés | MEDLINE | ID: mdl-28530241

RESUMEN

Adoptive T-cell immunotherapy is a promising approach to cancer therapy. Stem cell memory T (TSCM) cells have been proposed as a class of long-lived and highly proliferative memory T cells. CD8+ TSCM cells can be generated in vitro from naive CD8+ T cells via Wnt signalling; however, methods do not yet exist for inducing TSCM cells from activated or memory T cells. Here, we show a strategy for generating TSCM-like cells in vitro (iTSCM cells) from activated CD4+ and CD8+ T cells in mice and humans by coculturing with stromal cells that express a Notch ligand. iTSCM cells lose PD-1 and CTLA-4 expression, and produce a large number of tumour-specific effector cells after restimulation. This method could therefore be used to generate antigen-specific effector T cells for adoptive immunotherapy.


Asunto(s)
Inmunoterapia Adoptiva/métodos , Activación de Linfocitos , Receptores Notch/metabolismo , Linfocitos T/citología , Animales , Linfocitos T CD4-Positivos/citología , Linfocitos T CD8-positivos/citología , Antígeno CTLA-4/metabolismo , Diferenciación Celular , Línea Celular , Proliferación Celular , Separación Celular , Técnicas de Cocultivo , Citometría de Flujo , Homeostasis , Humanos , Memoria Inmunológica , Ligandos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Análisis de Secuencia por Matrices de Oligonucleótidos , Receptor de Muerte Celular Programada 1/metabolismo , Células Madre/citología
13.
Arthritis Res Ther ; 18: 167, 2016 07 13.
Artículo en Inglés | MEDLINE | ID: mdl-27411315

RESUMEN

BACKGROUND: The aim of this study was to elucidate the function of circulating follicular helper T (Tfh) cell subsets in helping B cells in patients with active, untreated IgG4-related disease (IgG4-RD) and determine their relationship with disease activity. METHODS: Seventeen consecutive patients with active, untreated IgG4-RD, 20 with primary Sjögren syndrome (pSS), 5 with multicentric Castleman's disease (MCD), and 12 healthy controls (HC) were enrolled. Tfh cell subset function was evaluated by co-culture with naïve B cells in vitro. Activated Tfh cell subsets were defined as a CCR7(low)PD-1(high) subset among Tfh cell subsets. Disease activity was evaluated by IgG4-RD responder index (IgG4-RD RI) score. RESULTS: The number of Tfh2 cells was significantly higher in IgG4-RD compared to pSS, MCD, or HC, and correlated with serum IgG4 level or the number of plasmablasts. In vitro, Tfh2 cells more efficiently induced the differentiation of naïve B cells into plasmablasts compared to Tfh1 or Tfh17 cells. Of note, while IgG production in culture supernatants of Tfh2 cells was comparable between IgG4-RD and HC, IgG4 production was significantly higher with Tfh2 cells from patients with IgG4-RD than in those from HC. Accordingly, the IgG4:IgG ratio in culture supernatants was also significantly higher with Tfh2 cells from IgG4-RD compared to HC. Moreover, the number of activated Tfh2 cells was higher in IgG4-RD compared to pSS, MCD, or HC, and strongly correlated with IgG4-RD RI score in the baseline active phase. Particularly, the number of activated Tfh2 cells was associated with the number of affected organs and serum IgG4 level. Importantly, the number of activated Tfh2 cells was decreased after glucocorticoid treatment and paralleled disease improvement. Moreover, the number of activated Tfh1 cells was also increased in IgG4-RD compared to pSS, MCD, or HC, correlating with IgG4-RD RI score, but not with serum IgG4 level. CONCLUSIONS: Tfh2 cells, but not Tfh1 or Tfh17 cells, induce the differentiation of naïve B cells into plasmablasts and enhanced production of IgG4 in patients with active, untreated IgG4-RD. Furthermore, activated Tfh2 cells reflect disease activity, suggesting the involvement of this T cell subset in the pathogenesis of IgG4-RD. Interestingly, the number of activated Tfh1 cells was also increased in IgG4-RD, correlating with disease activity but not with serum IgG4 level, suggesting the involvement of Tfh1 cells but not in the process of IgG4 production in patients with IgG4-RD.


Asunto(s)
Linfocitos B/inmunología , Enfermedades del Sistema Inmune/inmunología , Inmunoglobulina G/inmunología , Activación de Linfocitos/inmunología , Células TH1/inmunología , Células Th2/inmunología , Adulto , Anciano , Separación Celular , Técnicas de Cocultivo , Femenino , Citometría de Flujo , Humanos , Masculino , Persona de Mediana Edad
14.
Brain Res ; 994(1): 91-8, 2003 Dec 19.
Artículo en Inglés | MEDLINE | ID: mdl-14642452

RESUMEN

To investigate the effects of cilostazol on the hemispheric ischemic lesion, we monitored the apparent diffusion coefficient (ADC) and T2 images by MRI techniques in comparison with histology at the terminal of and after 24-h reperfusion following 2-h occlusion of middle cerebral artery (MCA). The ADC values of tissue water and T2-weighted images were quantified by high field magnetic resonance. No significant difference was observed by ADC image among vehicle and cilostazol treatment groups when measured during MCA occlusion. Oral treatment with cilostazol 30 mg/kg two times at 5 min and 4 h significantly suppressed the hemispheric lesion area and volumes when detected by ADC, T2 images and histology, but 3 and 10 mg/kg cilostazol were without effect. Cilostazol (30 mg/kg) significantly reduced the increased cerebral water content at the ischemic hemisphere compared with vehicle group. In line with these results, the neurological deteriorations were much improved in the cilostazol-treated group. Taken together, it is concluded that post-treatment with cilostazol exerts a potent protective effect against cerebral infarct size by reducing the cytotoxic edema.


Asunto(s)
Edema Encefálico/tratamiento farmacológico , Isquemia Encefálica/tratamiento farmacológico , Encéfalo/efectos de los fármacos , Tetrazoles/uso terapéutico , Animales , Encéfalo/patología , Edema Encefálico/patología , Isquemia Encefálica/patología , Cilostazol , Imagen por Resonancia Magnética/métodos , Masculino , Ratas , Ratas Sprague-Dawley , Tetrazoles/farmacología
15.
Aviat Space Environ Med ; 74(3): 207-11, 2003 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-12650266

RESUMEN

INTRODUCTION: The purpose of this study was to evaluate the effects of electrical stimulation on disuse-atrophied muscles. METHODS: Sprague-Dawley rats were used and divided into three groups: control (C), hind-limb suspended for 7 d (HS), and HS plus transcutaneous electrical stimulation for 7 d (ES). In the ES group, transcutaneous electrical stimulation was induced at 1 Hz for 1 h every day to condition the gastrocnemius-plantaris-soleus muscles. Muscle oxidative capacity was evaluated by 31P-MRS in vivo. Maximum tension and muscle wet mass were also measured. RESULTS: Muscle oxidative capacity decreased within 1 wk in HS; however, it was maintained when electric stimulation was applied to the suspended limb. The maximum twitch tension in HS was significantly smaller than that in C (p < 0.05), while in ES it did not differ from that in C. The muscle mass was significantly smaller in the HS and ES groups compared to C (p < 0.05). CONCLUSION: These data indicated that twitch electrical stimulation was effective in preventing deterioration of muscle functions, such as maximum tension and oxidative capacity, induced by 1 wk of disuse.


Asunto(s)
Músculo Esquelético/patología , Músculo Esquelético/fisiología , Trastornos Musculares Atróficos/prevención & control , Trastornos Musculares Atróficos/fisiopatología , Consumo de Oxígeno , Vuelo Espacial , Animales , Atrofia , Modelos Animales de Enfermedad , Estimulación Eléctrica , Masculino , Contracción Muscular/fisiología , Trastornos Musculares Atróficos/veterinaria , Ratas , Ratas Sprague-Dawley
17.
Acupunct Med ; 27(4): 155-62, 2009 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19942721

RESUMEN

BACKGROUND: Scalp acupuncture (SA) therapy on strokes has been empirically established and widely used in clinics in China. The evidence from clinical studies suggests that SA produces significant benefits for some patients with stroke. METHODS: The effect of scalp acupuncture was studied using MRI for two different stroke models: spontaneously hypertensive stroke-prone (SHR-SP) rats and rats with transiently induced focal cerebral ischaemia by middle cerebral artery occlusion for 2 h (MCAO rats). RESULTS: Stroke onset in SHR-SP rats was characterised by a development of vasogenic oedema without any appearance of cytotoxic oedema. Scalp acupuncture reduced rapidly neurological dysfunction in SHR-SP rats and reduced the volume of the vasogenic oedema during the same period. In contrast, in MCAO rats, focal cerebral ischaemia caused an immediate development of cytotoxic oedema without any appearance of vasogenic oedema. Vasogenic oedema developed after reperfusion. Scalp acupuncture had no significant effects on the cytotoxic oedema, vasogenic oedema or neurological dysfunction of the MCAO rats within the time span examined. CONCLUSION: Scalp acupuncture had a rapid and strong effect on neurological dysfunction only in the hypertensive stroke-model by reducing the vasogenic oedema. Our results suggest that, if there are similar underlying mechanisms in human strokes, scalp acupuncture may be more beneficial for patients with strokes of hypertension-caused vasogenic origin than ischaemic origin.


Asunto(s)
Terapia por Acupuntura/métodos , Isquemia Encefálica/terapia , Modelos Animales de Enfermedad , Infarto de la Arteria Cerebral Media/clasificación , Infarto de la Arteria Cerebral Media/terapia , Cuero Cabelludo , Puntos de Acupuntura , Animales , Encéfalo/fisiopatología , Isquemia Encefálica/complicaciones , China , Hipertensión/complicaciones , Infarto de la Arteria Cerebral Media/etiología , Imagen por Resonancia Magnética , Ratas , Ratas Endogámicas SHR
18.
J Biol Chem ; 283(22): 14955-62, 2008 May 30.
Artículo en Inglés | MEDLINE | ID: mdl-18400747

RESUMEN

It has been shown that transforming growth factor beta1 (TGF-beta1) is critical in the generation of CD4(+)CD25(+)Foxp3(+)-inducible regulatory T cells (iTregs) from naïve CD4(+)T cells. However, in contrast to natural Tregs, TGF-beta1-induced iTregs rapidly lose both Foxp3 expression and suppression activity. We found that TGF-beta1-induced Foxp3 levels were maintained by the addition of the anti-interleukin 4 (IL-4) antibody or by STAT6 gene deletion. Thus, IL-4 is an important suppressor of Foxp3 induction, and T helper 2 development is a major cause for the disappearance of iTreg during long culture. Using promoter analysis in EL4 cells and primary T cells, we identified a silencer region containing a STAT6 binding site. STAT6 binding to this site reduced TGF-beta1-mediated Foxp3 promoter activation and chromatin modification. Retinoic acid has also been shown to suppress loss of Foxp3 induced by TGF-beta1. Retinoic acid in the presence of TGF-beta1 reduced STAT6 binding to the Foxp3 promoter and enhanced histone acetylation, thereby reverting the effect of IL-4. We propose that antagonistic agents for neutralizing IL-4 could be a novel strategy to facilitate inducible Treg cell generation and the promotion of tolerance in Th2-dominated diseases such as allergy.


Asunto(s)
Factores de Transcripción Forkhead/metabolismo , Regiones Promotoras Genéticas , Receptores de Ácido Retinoico/metabolismo , Factor de Transcripción STAT6/metabolismo , Linfocitos T Reguladores/metabolismo , Células Th2/metabolismo , Factor de Crecimiento Transformador beta1/farmacología , Animales , Anticuerpos/farmacología , Células Cultivadas , Ensamble y Desensamble de Cromatina/inmunología , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/inmunología , Hipersensibilidad/inmunología , Hipersensibilidad/metabolismo , Hipersensibilidad/patología , Tolerancia Inmunológica/genética , Interleucina-4/inmunología , Interleucina-4/metabolismo , Interleucina-4/farmacología , Ratones , Ratones Noqueados , Regiones Promotoras Genéticas/inmunología , Receptores de Ácido Retinoico/genética , Receptores de Ácido Retinoico/inmunología , Factor de Transcripción STAT6/genética , Factor de Transcripción STAT6/inmunología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/patología , Células Th2/inmunología , Células Th2/patología , Factor de Crecimiento Transformador beta1/inmunología
19.
Int Immunol ; 19(5): 609-19, 2007 May.
Artículo en Inglés | MEDLINE | ID: mdl-17383969

RESUMEN

Signal transducer and activator of transcription 3 (STAT3) has been shown to mediate the anti-inflammatory effect of IL-10. Activated STAT3 suppresses LPS-induced IL-6, tumor necrosis factor-alpha and IL-12 gene expression in macrophages and dendritic cells. However, the mechanism of Toll-like receptor (TLR) signal suppression by STAT3 has not been clarified. In this study, we investigated the effect of constitutively activated STAT3 (STAT3C) on LPS-induced nuclear factor-kappaB (NF-kappaB) activation. The forced expression of STAT3C in HEK293/TLR4 cells, but neither wild-type STAT3 nor dominant-negative form of STAT3, suppressed LPS-TLR4-mediated NF-kappaB reporter activation. The over-expression of STAT3C did not affect the signal transduction of TLR4, such as the phosphorylation of inhibitory nuclear factor-kappaBalpha and mitogen-activated protein kinases and the DNA-binding activity of NF-kappaB. Thus, STAT3C could suppress the transcriptional and/or translational activity of NF-kappaB. To define the molecular mechanism, we searched STAT3C-binding proteins by using a proteomic approach and found that a novel RNA-binding protein, alphaCP-1, interacted with STAT3C. alphaCP-1 is a K-homology domain-containing RNA-binding protein with specificity for C-rich pyrimidine tracts. Such proteins play pivotal roles in a broad-spectrum of transcriptional and translational events. The over-expression of alphaCP-1 augmented the suppressive effect of STAT3C on NF-kappaB activation in HEK293/TLR4 cells. Furthermore, the forced expression of alphaCP-1 enhanced the antagonistic effect of IL-10 on IL-6 production in RAW264.7 cells, while small interfering RNA against alphaCP-1 reduced it. These data suggest that alphaCP-1 is involved in the STAT3-mediated suppression of NF-kappaB activity.


Asunto(s)
Proteínas Portadoras/metabolismo , Ribonucleoproteínas Nucleares Heterogéneas/metabolismo , FN-kappa B/antagonistas & inhibidores , Proteínas de Unión al ARN/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/fisiología , Transcripción Genética/fisiología , Animales , Clonación Molecular , Proteínas de Unión al ADN , Células Dendríticas , Regulación de la Expresión Génica , Humanos , Interleucina-10/genética , Interleucina-10/metabolismo , Interleucina-6/biosíntesis , Interleucina-6/genética , Ratones , FN-kappa B/genética , ARN Interferente Pequeño/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Receptores Toll-Like/metabolismo , Factor de Transcripción AP-1/metabolismo , Transfección , Células Tumorales Cultivadas
20.
Eur J Neurosci ; 23(4): 1077-81, 2006 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-16519673

RESUMEN

Mitochondrial dysfunction has been implicated in the death of nigrostriatal dopaminergic neurons in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated experimental models of Parkinson's disease (PD). Here we utilized proton magnetic resonance spectroscopy ((1)H MRS) to identify changes in energy metabolism in the striatum of MPTP-treated C57BL/6 mice. Remarkable increases in lactate/creatine (Lac/Cr) ratio were observed at 2 h and then quickly returned to about the basal level by 7 h after injection of MPTP. Neurochemical and Western blot analyses revealed that dopamine contents and protein levels of tyrosine hydroxylase and dopamine transporter in the striatum were profoundly decreased at 3 days after MPTP treatment. Pretreatment with deprenyl, a monoamine oxidase B inhibitor, or GBR-12909, a dopamine uptake inhibitor, almost completely attenuated both the increases in striatal Lac/Cr ratio and the subsequent loss of dopaminergic nerve terminals in MPTP-treated mice. The present study indicates that (1)H MRS is a sensitive measure of biochemical alterations of the brain in a mouse model of PD, and further shows that the increases in striatal Lac/Cr ratio induced by MPTP may be associated with mitochondrial energy crisis, followed by dopaminergic neurotoxicity.


Asunto(s)
Cuerpo Estriado/efectos de los fármacos , Ácido Láctico/metabolismo , Intoxicación por MPTP/metabolismo , Neurotoxinas/farmacología , Protones , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacología , Animales , Western Blotting/métodos , Química Encefálica/efectos de los fármacos , Cromatografía Líquida de Alta Presión/métodos , Dopamina/metabolismo , Inhibidores de Captación de Dopamina/farmacología , Interacciones Farmacológicas , Espectroscopía de Resonancia Magnética , Masculino , Ratones , Ratones Endogámicos C57BL , Fármacos Neuroprotectores/farmacología , Piperazinas/farmacología , Selegilina/farmacología , Factores de Tiempo
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