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Autor Iván Martínez Forero |
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Dynamic cross-regulation of antigen-specific effector and regulatory T cell subpopulations and microglia in brain autoimmunity / Iván Martínez Forero
Título : Dynamic cross-regulation of antigen-specific effector and regulatory T cell subpopulations and microglia in brain autoimmunity Tipo de documento : documento electrónico Autores : Iván Martínez Forero, Fecha de publicación : 2013 Títulos uniformes : BMC Systems Biology Idioma : Inglés (eng) Palabras clave : T cells effector regulatory B cells dynamics autoimmunity multiple sclerosis systems biology immunotherapy anti-CD20 Resumen : Background: Multiple Sclerosis (MS) is considered a T-cell-mediated autoimmune disease with a prototypical oscillatory behavior, as evidenced by the presence of clinical relapses. Understanding the dynamics of immune cells governing the course of MS, therefore, has many implications for immunotherapy. Here, we used flow cytometry to analyze the time-dependent behavior of antigen-specific effector (Teff) and regulatory (Treg) T cells and microglia in mice model of MS, Experimental Autoimmune Encephalomyelitis (EAE), and compared the observations with a mathematical cross-regulation model of T-cell dynamics in autoimmune disease. Results: We found that Teff and Treg cells specific to myelin olygodendrocyte glycoprotein (MOG) developed coupled oscillatory dynamics with a 4- to 5-day period and decreasing amplitude that was always higher for the Teff populations, in agreement with the mathematical model. Microglia activation followed the oscillations of MOG specific Teff cells in the secondary lymphoid organs, but they were activated before MOG-specific T-cell peaks in the CNS. Finally, we assessed the role of B-cell depletion induced by anti-CD20 therapy in the dynamics of T cells in anEAE model with more severe disease after therapy. We observed that B-cell depletion decreases Teff expansion, although its oscillatory behavior persists. However, the effect of B cell depletion was more significant in the Treg opulation within the CNS, which matched with activation of microglia and worsening of the disease. Mathematical modeling of T-cell cross-regulation after anti-CD20 therapy suggests that B-cell depletion maY influence the dynamics of T cells by fine-tuning their activation. Conclusions: The oscillatory dynamics of T-cells have an intrinsic origin in the physiological regulation of the adaptive immune response, which influences both disease phenotype and response to immunotherapy. Mención de responsabilidad : Sara Martinez-Pasamar, Elena Abad, Beatriz Moreno, Nieves Velez de Mendizabal, Ivan Martinez-Forero, Jordi Garcia-Ojalvo, Pablo Villoslada Referencia : BMC Syst Biol. 2013 Apr 26;7:34. DOI (Digital Object Identifier) : 10.1186/1752-0509-7-34|| PMID : 23618467 Derechos de uso : CC BY En línea : https://bmcsystbiol.biomedcentral.com/articles/10.1186/1752-0509-7-34 Enlace permanente : https://hospitalpablotobon.cloudbiteca.com/pmb/opac_css/index.php?lvl=notice_display&id=3671 Dynamic cross-regulation of antigen-specific effector and regulatory T cell subpopulations and microglia in brain autoimmunity [documento electrónico] / Iván Martínez Forero, . - 2013.
Obra : BMC Systems Biology
Idioma : Inglés (eng)
Palabras clave : T cells effector regulatory B cells dynamics autoimmunity multiple sclerosis systems biology immunotherapy anti-CD20 Resumen : Background: Multiple Sclerosis (MS) is considered a T-cell-mediated autoimmune disease with a prototypical oscillatory behavior, as evidenced by the presence of clinical relapses. Understanding the dynamics of immune cells governing the course of MS, therefore, has many implications for immunotherapy. Here, we used flow cytometry to analyze the time-dependent behavior of antigen-specific effector (Teff) and regulatory (Treg) T cells and microglia in mice model of MS, Experimental Autoimmune Encephalomyelitis (EAE), and compared the observations with a mathematical cross-regulation model of T-cell dynamics in autoimmune disease. Results: We found that Teff and Treg cells specific to myelin olygodendrocyte glycoprotein (MOG) developed coupled oscillatory dynamics with a 4- to 5-day period and decreasing amplitude that was always higher for the Teff populations, in agreement with the mathematical model. Microglia activation followed the oscillations of MOG specific Teff cells in the secondary lymphoid organs, but they were activated before MOG-specific T-cell peaks in the CNS. Finally, we assessed the role of B-cell depletion induced by anti-CD20 therapy in the dynamics of T cells in anEAE model with more severe disease after therapy. We observed that B-cell depletion decreases Teff expansion, although its oscillatory behavior persists. However, the effect of B cell depletion was more significant in the Treg opulation within the CNS, which matched with activation of microglia and worsening of the disease. Mathematical modeling of T-cell cross-regulation after anti-CD20 therapy suggests that B-cell depletion maY influence the dynamics of T cells by fine-tuning their activation. Conclusions: The oscillatory dynamics of T-cells have an intrinsic origin in the physiological regulation of the adaptive immune response, which influences both disease phenotype and response to immunotherapy. Mención de responsabilidad : Sara Martinez-Pasamar, Elena Abad, Beatriz Moreno, Nieves Velez de Mendizabal, Ivan Martinez-Forero, Jordi Garcia-Ojalvo, Pablo Villoslada Referencia : BMC Syst Biol. 2013 Apr 26;7:34. DOI (Digital Object Identifier) : 10.1186/1752-0509-7-34|| PMID : 23618467 Derechos de uso : CC BY En línea : https://bmcsystbiol.biomedcentral.com/articles/10.1186/1752-0509-7-34 Enlace permanente : https://hospitalpablotobon.cloudbiteca.com/pmb/opac_css/index.php?lvl=notice_display&id=3671 Reserva
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Código de barras Número de Ubicación Tipo de medio Ubicación Sección Estado DD000244 AC-2013-012 Archivo digital Producción Científica Artículos científicos Disponible Documentos electrónicos
2013-012.pdfAdobe Acrobat PDF T cell costimulation with anti-CD137 monoclonal antibodies is mediated by K63-polyubiquitin-dependent signals from endosomes / Iván Martínez Forero
Título : T cell costimulation with anti-CD137 monoclonal antibodies is mediated by K63-polyubiquitin-dependent signals from endosomes Tipo de documento : documento electrónico Autores : Iván Martínez Forero, Fecha de publicación : 2013 Títulos uniformes : Journal of Immunology Idioma : Inglés (eng) Resumen : Agonist anti-CD137 (4-1BB) mAbs enhance CD8-mediated antitumor immunity. Agonist anti-human CD137 mAbs binding to four distinct epitopes on the CD137 glycoprotein costimulated T cell activation irrespective of the engaged epitope or its interference with CD137L binding. CD137 perturbation with all these agonist mAbs resulted in Ag and Ab internalization toward an endosomal vesicular compartment. Internalization was observed in activated T lymphocytes from humans and mice, not only in culture but also in Ab-injected living animals. These in vivo experiments were carried out upon systemic i.v. injections with anti-CD137 mAbs and showed CD137 internalization in tumor-infiltrating lymphocytes and in activated human T cells transferred to immunodeficient mice. Efficient CD137 internalization required K63 polyubiquitination and endocytosed CD137-containing vesicles recruited TNFR-associated factor (TRAF) 2 and were decorated with K63 polyubiquitins. CD137 stimulation activates NF-κB through a K63-linked polyubiquitination-dependent route, and CD137-associated TRAF2 becomes K63 polyubiquitinated. Consistent with a role for TRAF2 in CD137 signaling, transgenic mice functionally deficient in TRAF2 showed delayed immunotherapeutic activity of anti-CD137 mAbs. As a whole, these findings advance our knowledge of the mechanisms of action of anti-CD137 immunostimulatory mAbs such as those currently undergoing clinical trials in cancer patients. Mención de responsabilidad : Ivan Martinez-Forero, Arantza Azpilikueta, Elixabet Bolaños-Mateo, Estanislao Nistal-Villan, Asis Palazon, Alvaro Teijeira, Gema Perez-Chacon, Aizea Morales-Kastresana, Oihana Murillo, Maria Jure-Kunkel, Juan M Zapata, Ignacio Melero Referencia : J Immunol. 2013 Jun 15;190(12):6694-706. DOI (Digital Object Identifier) : 10.4049/jimmunol.1203010 PMID : 23690480 En línea : https://www.jimmunol.org/content/190/12/6694 Enlace permanente : https://hospitalpablotobon.cloudbiteca.com/pmb/opac_css/index.php?lvl=notice_display&id=3675 T cell costimulation with anti-CD137 monoclonal antibodies is mediated by K63-polyubiquitin-dependent signals from endosomes [documento electrónico] / Iván Martínez Forero, . - 2013.
Obra : Journal of Immunology
Idioma : Inglés (eng)
Resumen : Agonist anti-CD137 (4-1BB) mAbs enhance CD8-mediated antitumor immunity. Agonist anti-human CD137 mAbs binding to four distinct epitopes on the CD137 glycoprotein costimulated T cell activation irrespective of the engaged epitope or its interference with CD137L binding. CD137 perturbation with all these agonist mAbs resulted in Ag and Ab internalization toward an endosomal vesicular compartment. Internalization was observed in activated T lymphocytes from humans and mice, not only in culture but also in Ab-injected living animals. These in vivo experiments were carried out upon systemic i.v. injections with anti-CD137 mAbs and showed CD137 internalization in tumor-infiltrating lymphocytes and in activated human T cells transferred to immunodeficient mice. Efficient CD137 internalization required K63 polyubiquitination and endocytosed CD137-containing vesicles recruited TNFR-associated factor (TRAF) 2 and were decorated with K63 polyubiquitins. CD137 stimulation activates NF-κB through a K63-linked polyubiquitination-dependent route, and CD137-associated TRAF2 becomes K63 polyubiquitinated. Consistent with a role for TRAF2 in CD137 signaling, transgenic mice functionally deficient in TRAF2 showed delayed immunotherapeutic activity of anti-CD137 mAbs. As a whole, these findings advance our knowledge of the mechanisms of action of anti-CD137 immunostimulatory mAbs such as those currently undergoing clinical trials in cancer patients. Mención de responsabilidad : Ivan Martinez-Forero, Arantza Azpilikueta, Elixabet Bolaños-Mateo, Estanislao Nistal-Villan, Asis Palazon, Alvaro Teijeira, Gema Perez-Chacon, Aizea Morales-Kastresana, Oihana Murillo, Maria Jure-Kunkel, Juan M Zapata, Ignacio Melero Referencia : J Immunol. 2013 Jun 15;190(12):6694-706. DOI (Digital Object Identifier) : 10.4049/jimmunol.1203010 PMID : 23690480 En línea : https://www.jimmunol.org/content/190/12/6694 Enlace permanente : https://hospitalpablotobon.cloudbiteca.com/pmb/opac_css/index.php?lvl=notice_display&id=3675 Reserva
Reservar este documentoEjemplares(1)
Código de barras Número de Ubicación Tipo de medio Ubicación Sección Estado DD000248 AC-2013-016 Archivo digital Producción Científica Artículos científicos Disponible