Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 11 de 11
Filtrar
1.
Immunity ; 36(3): 438-50, 2012 Mar 23.
Artículo en Inglés | MEDLINE | ID: mdl-22444632

RESUMEN

Central tolerance can be mediated by peripheral dendritic cells (DCs) that transport innocuous antigens (Ags) to the thymus for presentation to developing T cells, but the responsible DC subsets remained poorly defined. Immature plasmacytoid DCs (pDCs) express CCR9, a chemokine receptor involved in migration of T cell precursors to the thymus. We show here that CCR9 mediated efficient thymic entry of endogenous or i.v. transfused pDCs. pDCs activated by Toll-like receptor (TLR) ligands downregulated CCR9 and lost their ability to home to the thymus. Moreover, endogenous pDCs took up subcutaneously injected fluorescent Ag and, in the absence of TLR signals, transported Ag to the thymus in a CCR9-dependent fashion. Injected, Ag-loaded pDCs effectively deleted Ag-specific thymocytes, and this thymic clonal deletion required CCR9-mediated homing and was prevented by infectious signals. Thus, peripheral pDCs can contribute to immune tolerance through CCR9-dependent transport of peripheral Ags and subsequent deletion of Ag-reactive thymocytes.


Asunto(s)
Autoantígenos/metabolismo , Células Dendríticas/inmunología , Autotolerancia/inmunología , Timo/inmunología , Animales , Transporte Biológico Activo , Supresión Clonal/inmunología , Islas de CpG/inmunología , Endocitosis , Ratones , Ratones Congénicos , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores CCR/deficiencia , Receptores CCR/genética , Receptores CCR/metabolismo , Transducción de Señal/inmunología , Solubilidad , Linfocitos T/inmunología , Receptores Toll-Like/metabolismo
2.
Nat Immunol ; 9(11): 1253-60, 2008 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-18836452

RESUMEN

Dendritic cells (DCs) are 'professional' antigen-presenting cells that are key in the regulation of immune responses. Here we characterize a unique subset of tolerogenic DCs that expressed the chemokine receptor CCR9 and migrated to the CCR9 ligand CCL25, a chemokine linked to the homing of T cells and DCs to the gut. CCR9(+) DCs were of the plasmacytoid DC (pDC) lineage, had an immature phenotype and rapidly downregulated CCR9 in response to maturation-inducing pDC-restricted Toll-like receptor ligands. CCR9(+) pDCs were potent inducers of regulatory T cell function and suppressed antigen-specific immune responses both in vitro and in vivo, including inhibiting acute graft-versus-host disease induced by allogeneic CD4(+) donor T cells in irradiated recipients. Our results identify a highly immunosuppressive population of pDCs present in lymphoid tissues.


Asunto(s)
Células Dendríticas/inmunología , Enfermedad Injerto contra Huésped/inmunología , Receptores CCR10/inmunología , Autotolerancia , Tolerancia al Trasplante , Animales , Biomarcadores/metabolismo , Diferenciación Celular , Línea Celular Tumoral , Movimiento Celular , Quimiocinas CC/metabolismo , Células Dendríticas/metabolismo , Regulación hacia Abajo , Intestinos/inmunología , Antígenos Comunes de Leucocito/metabolismo , Ligandos , Ratones , Ratones Congénicos , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Receptores CCR10/metabolismo , Linfocitos T Reguladores/inmunología , Receptores Toll-Like/metabolismo , Receptor de Quimiocina D6
3.
Mol Ther ; 26(5): 1354-1365, 2018 05 02.
Artículo en Inglés | MEDLINE | ID: mdl-29606504

RESUMEN

Glioblastoma (GBM) is the least treatable type of brain tumor, afflicting over 15,000 people per year in the United States. Patients have a median survival of 16 months, and over 95% die within 5 years. The chemokine receptor ACKR3 is selectively expressed on both GBM cells and tumor-associated blood vessels. High tumor expression of ACKR3 correlates with poor prognosis and potential treatment resistance, making it an attractive therapeutic target. We engineered a single chain FV-human FC-immunoglobulin G1 (IgG1) antibody, X7Ab, to target ACKR3 in human and mouse GBM cells. We used hydrodynamic gene transfer to overexpress the antibody, with efficacy in vivo. X7Ab kills GBM tumor cells and ACKR3-expressing vascular endothelial cells by engaging the cytotoxic activity of natural killer (NK) cells and complement and the phagocytic activity of macrophages. Combining X7Ab with TMZ allows the TMZ dosage to be lowered, without compromising therapeutic efficacy. Mice treated with X7Ab and in combination with TMZ showed significant tumor reduction by MRI and longer survival overall. Brain-tumor-infiltrating leukocyte analysis revealed that X7Ab enhances the activation of M1 macrophages to support anti-tumor immune response in vivo. Targeting ACKR3 with immunotherapeutic monoclonal antibodies (mAbs) in combination with standard of care therapies may prove effective in treating GBM.


Asunto(s)
Anticuerpos Monoclonales/farmacología , Glioblastoma/inmunología , Glioblastoma/metabolismo , Receptores CXCR/antagonistas & inhibidores , Temozolomida/farmacología , Animales , Anticuerpos Monoclonales/metabolismo , Afinidad de Anticuerpos/inmunología , Antineoplásicos Inmunológicos/farmacología , Línea Celular Tumoral , Citotoxicidad Inmunológica/efectos de los fármacos , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Glioblastoma/diagnóstico , Glioblastoma/mortalidad , Humanos , Imagen por Resonancia Magnética , Ratones , Mortalidad , Unión Proteica/inmunología , Receptores CXCR/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
4.
J Immunol ; 190(12): 6126-34, 2013 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-23677472

RESUMEN

Ag-presenting dendritic cells (DCs) interpret environmental signals to orchestrate local and systemic immune responses. They govern the balance between tolerance and inflammation at epithelial surfaces, where the immune system must provide robust pathogen responses while maintaining tolerance to commensal flora and food Ags. The Wnt family of secreted proteins, which control epithelial and hematopoietic development and homeostasis, is emerging as an important regulator of inflammation. In this study, we show that canonical and noncanonical Wnts directly stimulate murine DC production of anti-inflammatory cytokines. Wnt3A triggers canonical ß-catenin signaling and preferentially induces DC TGF-ß and VEGF production, whereas Wnt5A induces IL-10 through alternative pathways. The Wnts also alter DC responses to microbe- or pathogen-associated molecular patterns, inhibiting proinflammatory cytokine induction in response to TLR ligands and promoting DC generation of Foxp3(+) regulatory T cells. Moreover, although both Wnts suppress proinflammatory responses to bacterial endotoxin and to TLR1/2, TLR7, and TLR9 ligands, Wnt5A, but not Wnt3A, inhibits IL-6 production in response to the viral mimic, polyinosinic:polycytidylic acid. Thus, Wnt family members directly and differentially regulate DC functions, an ability that may contribute to the balance between tolerance and inflammation at epithelial sites of exposure to microbes and environmental Ags.


Asunto(s)
Células Dendríticas/inmunología , Tolerancia Inmunológica/inmunología , Transducción de Señal/inmunología , Proteínas Wnt/inmunología , Animales , Presentación de Antígeno/inmunología , Diferenciación Celular/inmunología , Citocinas/biosíntesis , Citocinas/inmunología , Células Dendríticas/citología , Células Dendríticas/metabolismo , Ensayo de Inmunoadsorción Enzimática , Ratones , Ratones Endogámicos C57BL , Análisis por Matrices de Proteínas , Proteínas Wnt/metabolismo
5.
Front Oncol ; 11: 711673, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34381732

RESUMEN

Toll-like receptor (TLR) agonists have received considerable attention as therapeutic targets for cancer immunotherapy owing to their ability to convert immunosuppressive tumor microenvironments towards a more T-cell inflamed phenotype. However, TLRs differ in their cell expression profiles and intracellular signaling pathways, raising the possibility that distinct TLRs differentially influence the tumor immune microenvironment. Using single-cell RNA-sequencing, we address this by comparing the tumor immune composition of B16F10 melanoma following treatment with agonists of TLR3, TLR7, and TLR9. Marked differences are observed between treatments, including decreased tumor-associated macrophages upon TLR7 agonist treatment. A biased type-1 interferon signature is elicited upon TLR3 agonist treatment as opposed to a type-2 interferon signature with TLR9 agonists. TLR3 stimulation was associated with increased macrophage antigen presentation gene expression and decreased expression of PD-L1 and the inhibitory receptors Pirb and Pilra on infiltrating monocytes. Furthermore, in contrast to TLR7 and TLR9 agonists, TLR3 stimulation ablated FoxP3 positive CD4 T cells and elicited a distinct CD8 T cell activation phenotype highlighting the potential for distinct synergies between TLR agonists and combination therapy agents.

6.
Cancer Cell ; 39(10): 1404-1421.e11, 2021 10 11.
Artículo en Inglés | MEDLINE | ID: mdl-34520734

RESUMEN

The CDK4/6 inhibitor, palbociclib (PAL), significantly improves progression-free survival in HR+/HER2- breast cancer when combined with anti-hormonals. We sought to discover PAL resistance mechanisms in preclinical models and through analysis of clinical transcriptome specimens, which coalesced on induction of MYC oncogene and Cyclin E/CDK2 activity. We propose that targeting the G1 kinases CDK2, CDK4, and CDK6 with a small-molecule overcomes resistance to CDK4/6 inhibition. We describe the pharmacodynamics and efficacy of PF-06873600 (PF3600), a pyridopyrimidine with potent inhibition of CDK2/4/6 activity and efficacy in multiple in vivo tumor models. Together with the clinical analysis, MYC activity predicts (PF3600) efficacy across multiple cell lineages. Finally, we find that CDK2/4/6 inhibition does not compromise tumor-specific immune checkpoint blockade responses in syngeneic models. We anticipate that (PF3600), currently in phase 1 clinical trials, offers a therapeutic option to cancer patients in whom CDK4/6 inhibition is insufficient to alter disease progression.


Asunto(s)
Ciclo Celular/efectos de los fármacos , Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Femenino , Humanos , Masculino , Neoplasias/inmunología
7.
Eur J Immunol ; 39(4): 1078-87, 2009 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-19283777

RESUMEN

Repeated immunization of mice with bacterial superantigens induces extensive deletion and anergy of reactive CD4 T cells. Here we report that the in vitro proliferation anergy of CD4 T cells from TCR transgenic mice immunized three times with staphylococcal enterotoxin B (SEB) (3 x SEB) is partially due to an increased frequency of Foxp3(+) CD4 T cells. Importantly, reduced number of conventional CD25(-) Foxp3(-) cells, rather than conversion of such cells to Foxp3(+) cells, was the cause of that increase and was also seen in mice repeatedly immunized with OVA (3 x OVA) and OVA-peptide (OVAp) (3 x OVAp). Cell-transfer experiments revealed profound but transient anergy of CD4 T cells isolated from 3 x OVAp and 3x SEB mice. However, the in vivo anergy was CD4 T-cell autonomous and independent of Foxp3(+) Treg. Finally, proliferation of transferred CD4 T cells was inhibited in repeatedly immunized mice but inhibition was lost when transfer was delayed, despite the maintenance of elevated frequency of Foxp3(+) cells. These data provide important implications for Foxp3(+) cell-mediated tolerance in situations of repeated antigen exposure such as human persistent infections.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Anergia Clonal/inmunología , Factores de Transcripción Forkhead/inmunología , Linfocitos T Reguladores/inmunología , Animales , Proliferación Celular , Enterotoxinas/inmunología , Inmunización , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Ovalbúmina/inmunología , Superantígenos/inmunología
8.
Nat Commun ; 9(1): 1988, 2018 05 18.
Artículo en Inglés | MEDLINE | ID: mdl-29777108

RESUMEN

Lung cancer is the leading cause of cancer-related deaths worldwide, and lung squamous carcinomas (LUSC) represent about 30% of cases. Molecular aberrations in lung adenocarcinomas have allowed for effective targeted treatments, but corresponding therapeutic advances in LUSC have not materialized. However, immune checkpoint inhibitors in sub-populations of LUSC patients have led to exciting responses. Using computational analyses of The Cancer Genome Atlas, we identified a subset of LUSC tumors characterized by dense infiltration of inflammatory monocytes (IMs) and poor survival. With novel, immunocompetent metastasis models, we demonstrated that tumor cell derived CCL2-mediated recruitment of IMs is necessary and sufficient for LUSC metastasis. Pharmacologic inhibition of IM recruitment had substantial anti-metastatic effects. Notably, we show that IMs highly express Factor XIIIA, which promotes fibrin cross-linking to create a scaffold for LUSC cell invasion and metastases. Consistently, human LUSC samples containing extensive cross-linked fibrin in the microenvironment correlated with poor survival.


Asunto(s)
Carcinoma de Células Escamosas/inmunología , Factor XIIIa/inmunología , Fibrina/química , Neoplasias Pulmonares/inmunología , Monocitos/inmunología , Animales , Biomarcadores de Tumor/química , Biomarcadores de Tumor/inmunología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Quimiocina CCL2/genética , Quimiocina CCL2/inmunología , Factor XIIIa/genética , Femenino , Fibrina/inmunología , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Ratones , Ratones Endogámicos DBA , Invasividad Neoplásica
9.
Transplantation ; 82(11): 1493-500, 2006 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-17164722

RESUMEN

BACKGROUND: Previous studies have demonstrated that anti-CD40L or anti-B7 requires the presence of CD4(+)CD25(+) regulatory T cells (Treg) to induce antigen specific hyporesponsiveness. Other tolerance strategies involving Treg have shown a dependency on interleukin (IL)-10. The objective of this study was to investigate the role of CD4(+)CD25(+) Treg and IL-10 when treating transplant recipients with cytotoxic T lymphocyte-associated antigen (CTLA)-4 immunoglobulin (Ig), anti-CD40L, and anti-lymphocyte function-associated antigen (LFA)-1. METHODS: Recombinase activating gene-deficient (Rag1(-/-) mice were transplanted with BALB/c hearts and adoptively transferred with IL-10(-/-) CD4(+) T cells, CD4(+)CD25(-) T cells or CD4(+)CD25(-)CD103(-) T cells and treated with costimulation blockade. Intragraft T cells from C57BL/6 recipients were analyzed for the expression of the Foxp3 protein after tolerance induction. RESULTS: Mice reconstituted with IL-10(-/-) CD4(+) T cells, CD4(+)CD25(-) T cells or CD4(+)CD25(-) CD103(-) T cells and treated with costimulation blockade accepted allografts permanently. Analysis of cells from recipient mice adoptively transferred with CD4(+)CD25(-) T cells contained a population of CD4(low)CD25(+) T cells 100 days after transplantation. Costimulation blockade partially prevented the homeostatic proliferation of CD4(+)CD25(-)CD103(-) T cells in Rag-1(-/-) recipients. Accepted allografts contained an elevated number of CD4(+)Foxp3(+) T cells. CONCLUSIONS: These results indicate that T-cell derived IL-10 is not essential for induction of graft acceptance in mice treated with costimulation blockade, but that treatment limits T-cell expansion in the recipients. The results further indicate that tolerance is maintained by intragraft CD4(+)Foxp3(+) T cells.


Asunto(s)
Antígenos CD/farmacología , Antígenos de Diferenciación/farmacología , Supervivencia de Injerto/efectos de los fármacos , Trasplante de Corazón/inmunología , Inmunoglobulina G/farmacología , Linfocitos T Reguladores/efectos de los fármacos , Tolerancia al Trasplante , Animales , Antígenos CD4/análisis , Ligando de CD40/antagonistas & inhibidores , Ligando de CD40/inmunología , Antígeno CTLA-4 , Femenino , Factores de Transcripción Forkhead/análisis , Factores de Transcripción Forkhead/metabolismo , Genes RAG-1/genética , Supervivencia de Injerto/inmunología , Interleucina-10/genética , Subunidad alfa del Receptor de Interleucina-2/análisis , Antígeno-1 Asociado a Función de Linfocito/efectos de los fármacos , Antígeno-1 Asociado a Función de Linfocito/inmunología , Ratones , Ratones Mutantes , Trasplante de Piel , Linfocitos T Reguladores/inmunología
10.
J Immunol Methods ; 413: 69-73, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-25066631

RESUMEN

Due to low numbers of endogenous dendritic cells (DCs) in vivo, exogenous DC-poietin Fms-like tyrosine kinase 3-ligand (FLT3L) is routinely used to generate DC for subsequent studies. We engineered a novel FLT3L-FC DNA construct that, when combined with hydrodynamic gene transfer (HDT), induced robust DC expansion in mice. DC generated in vivo by FLT3L-FC HDT produced cytokines in response to stimulation by an array of TLR agonists and promoted T cell proliferation. The FLT3L-FC protein produced in vivo spontaneously homodimerized to enable effective FLT signaling and the FC-domain enhanced its plasma half-life, providing an improved reagent and method to boost DC numbers.


Asunto(s)
Células Dendríticas/inmunología , Técnicas de Transferencia de Gen , Proteínas de la Membrana/genética , Plásmidos/metabolismo , Proteínas Recombinantes de Fusión/genética , Animales , Recuento de Células , Proliferación Celular , Células Dendríticas/citología , Femenino , Expresión Génica , Semivida , Hidrodinámica , Proteínas de la Membrana/inmunología , Ratones , Ratones Endogámicos BALB C , Multimerización de Proteína , Proteínas Recombinantes de Fusión/inmunología , Transducción de Señal
11.
Immunology ; 118(2): 240-9, 2006 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-16771859

RESUMEN

We have previously demonstrated that CD4+ CD25+ natural regulatory T cells (Treg cells) induce down-modulation of CD80 and CD86 (B7) molecules on dendritic cells (DCs) in vitro. In this report we show that the extent of down-modulation is functionally significant because Treg-cell conditioned DCs induced poor T-cell proliferation responses. Further, we report that down-modulation was induced rapidly and was inhibited by blocking cytotoxic T lymphocyte antigen-4 (CTLA-4), which is constitutively expressed by the Treg cells. Even though Treg cells have previously been reported to kill antigen-presenting cells, the down-modulation was not due to selective killing of DCs expressing high level of the costimulatory molecules. We propose that Treg cells down-modulate B7-molecules on DCs in a CTLA-4-dependent way, thereby enhancing suppression of T-cell activity.


Asunto(s)
Antígenos de Diferenciación/inmunología , Linfocitos T CD4-Positivos/inmunología , Células Dendríticas/inmunología , Tolerancia Inmunológica , Subgrupos de Linfocitos T/inmunología , Animales , Presentación de Antígeno/inmunología , Antígenos CD , Antígeno B7-1/metabolismo , Antígeno B7-2/metabolismo , Antígeno CTLA-4 , Supervivencia Celular/inmunología , Células Cultivadas , Regulación hacia Abajo/inmunología , Femenino , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Receptores de Interleucina-2/análisis , Linfocitos T Reguladores/inmunología
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA