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1.
Blood ; 119(6): 1428-39, 2012 Feb 09.
Artículo en Inglés | MEDLINE | ID: mdl-22184407

RESUMEN

Adenosine acts as anti-inflammatory mediator on the immune system and has been described in regulatory T cell (Treg)-mediated suppression. In the absence of adenosine deaminase (ADA), adenosine and other purine metabolites accumulate, leading to severe immunodeficiency with recurrent infections (ADA-SCID). Particularly ADA-deficient patients with late-onset forms and after enzyme replacement therapy (PEG-ADA) are known to manifest immune dysregulation. Herein we provide evidence that alterations in the purine metabolism interfere with Treg function, thereby contributing to autoimmune manifestations in ADA deficiency. Tregs isolated from PEG-ADA-treated patients are reduced in number and show decreased suppressive activity, whereas they are corrected after gene therapy. Untreated murine ADA(-/-) Tregs show alterations in the plasma membrane CD39/CD73 ectonucleotidase machinery and limited suppressive activity via extracellular adenosine. PEG-ADA-treated mice developed multiple autoantibodies and hypothyroidism in contrast to mice treated with bone marrow transplantation or gene therapy. Tregs isolated from PEG-ADA-treated mice lacked suppressive activity, suggesting that this treatment interferes with Treg functionality. The alterations in the CD39/CD73 adenosinergic machinery and loss of function in ADA-deficient Tregs provide new insights into a predisposition to autoimmunity and the underlying mechanisms causing defective peripheral tolerance in ADA-SCID.


Asunto(s)
5'-Nucleotidasa/inmunología , Adenosina/inmunología , Agammaglobulinemia/inmunología , Antígenos CD/inmunología , Apirasa/inmunología , Inmunodeficiencia Combinada Grave/inmunología , Linfocitos T Reguladores/inmunología , 5'-Nucleotidasa/metabolismo , Adenosina/metabolismo , Adenosina Desaminasa/deficiencia , Adenosina Desaminasa/genética , Adenosina Desaminasa/inmunología , Adenosina Desaminasa/metabolismo , Adenosina Desaminasa/uso terapéutico , Adolescente , Adulto , Agammaglobulinemia/genética , Agammaglobulinemia/terapia , Animales , Antígenos CD/metabolismo , Apirasa/metabolismo , Autoanticuerpos/inmunología , Niño , Preescolar , Femenino , Factores de Transcripción Forkhead/inmunología , Factores de Transcripción Forkhead/metabolismo , Terapia Genética/métodos , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Hipotiroidismo/enzimología , Hipotiroidismo/genética , Hipotiroidismo/inmunología , Inmunohistoquímica , Lactante , Masculino , Ratones , Ratones Noqueados , Polietilenglicoles/química , Inmunodeficiencia Combinada Grave/genética , Inmunodeficiencia Combinada Grave/terapia , Linfocitos T Reguladores/metabolismo
2.
J Exp Med ; 208(3): 469-78, 2011 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-21339327

RESUMEN

Pancreatic cancer is a very aggressive disease characterized by a marked desmoplasia with a predominant Th2 (GATA-3+) over Th1 (T-bet+) lymphoid infiltrate. We found that the ratio of GATA-3+/T-bet+ tumor-infiltrating lymphoid cells is an independent predictive marker of patient survival. Patients surgically treated for stage IB/III disease with a ratio inferior to the median value had a statistically significant prolonged overall survival, implying an active role for Th2 responses in disease progression. Thymic stromal lymphopoietin (TSLP), which favors Th2 cell polarization through myeloid dendritic cell (DC) conditioning, was secreted by cancer-associated fibroblasts (CAFs) after activation with tumor-derived tumor necrosis factor α and interleukin 1ß. TSLP-containing supernatants from activated CAFs induced in vitro myeloid DCs to up-regulate the TSLP receptor (TSLPR), secrete Th2-attracting chemokines, and acquire TSLP-dependent Th2-polarizing capability in vitro. In vivo, Th2 chemoattractants were expressed in the tumor and in the stroma, and TSLPR-expressing DCs were present in the tumor stroma and in tumor-draining but not in nondraining lymph nodes. Collectively, this study identifies in pancreatic cancer a cross talk between tumor cells and CAFs, resulting in a TSLP-dependent induction of Th2-type inflammation which associates with reduced patient survival. Thus, blocking TSLP production by CAFs might help to improve prognosis in pancreatic cancer.


Asunto(s)
Citocinas/fisiología , Neoplasias Pancreáticas/inmunología , Células Th2/inmunología , Citocinas/biosíntesis , Femenino , Fibroblastos/metabolismo , Fibroblastos/fisiología , Humanos , Interleucina-1beta/fisiología , Linfocitos Infiltrantes de Tumor/fisiología , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/fisiopatología , Receptores de Citocinas/fisiología , Células TH1/inmunología , Células TH1/fisiología , Células Th2/fisiología , Factor de Necrosis Tumoral alfa/fisiología , Linfopoyetina del Estroma Tímico
3.
Clin Cancer Res ; 16(3): 800-13, 2010 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-20103663

RESUMEN

PURPOSE: Cancer stem cells (CSC) have been isolated from human tumors, including glioblastoma multiforme (GBM). The aims of this study were the immunobiological characterization of GBM CSCs and the assessment of whether these cells represent suitable targets for immunotherapy. EXPERIMENTAL DESIGN: GBM CSC lines and their fetal bovine serum (FBS)-cultured non-CSC pair lines were generated and examined by flow cytometry for expression of known tumor antigens, MHC-I and MHC-II molecules, antigen-processing machinery components, and NKG2D ligands. In addition, immunogenicity and immunosuppression of such cell lines for autologous or allogeneic T lymphocytes were tested by cytokine secretion (ELISPOT) or proliferation (carboxyfluorescein diacetate succinimidyl ester) assays, respectively. RESULTS: Both GBM CSC and FBS lines were weakly positive and negative for MHC-I, MHC-II, and NKG2D ligand molecules, respectively. Antigen-processing machinery molecules were also defective in both cell types. Upregulation of most molecules was induced by IFNs or 5-Aza deoxycytidine, although more efficiently in FBS than in CSCs. Patient T-cell responses, mediated by both TH1 and the TH2 subsets, against autologous CSC could be induced in vitro. In addition, CSC but not their paired FBS tumor lines inhibited T-cell proliferation of healthy donors. Notably, a differential gene signature that was confirmed at the protein levels for some immunologic-related molecules was also found between CSC and FBS lines. CONCLUSIONS: These results indicate lower immunogenicity and higher suppressive activity of GBM CSC compared with FBS lines. The immunogenicity, however, could be rescued by immune modulation leading to anti-GBM T cell-mediated immune response.


Asunto(s)
Neoplasias Encefálicas/patología , Glioblastoma/patología , Células Madre Neoplásicas/patología , Presentación de Antígeno , Línea Celular Tumoral , Perfilación de la Expresión Génica , Antígenos de Histocompatibilidad Clase I/metabolismo , Antígenos de Histocompatibilidad Clase II/metabolismo , Humanos , Linfocitos T/inmunología
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