RESUMEN
In persistent hepatitis C virus (HCV) infection, HCV-specific cytotoxic T lymphocyte (CTL) reactivity is impaired and this affects HCV control. Interleukin-7 receptor (CD127) expression on these cells could regulate CTL reactivity through Mcl-1/Bim balance modulation. Bim is a pro-apoptotic molecule blocked by the action of Mcl-1. Mcl-1/Bim expression and T cell reactivity on HCV-specific CTLs were compared according to CD127 phenotype. Peripheral blood lymphocytes (PBL) from HLA-A2(+) HCV(+) patients were obtained. HCV-specific CTLs were visualized by staining PBL with anti-CD8 and HLA-A2/peptide pentameric complexes (pentamer). Mcl-1/Bim/CD127 phenotype of HCV-specific CTLs was tested by staining detectable CD8(+)/pentamer(+) cells with anti-Mcl-1/Bim/CD127 antibodies. HCV-specific CTL proliferation ability after specific in vitro challenge was tested in the presence and absence of pancaspase inhibitor z-VAD-fmk. All stained cells were analysed by flow cytometry. CD127(low)-expressing HCV-specific CTLs associated with high HCV viraemia, while CD127(high) correlated with undetectable viral loads (P < 0.001). Directly ex vivo, pentamer(+) cell frequency was similar according to CD127 expression level. Nevertheless, CD127(low) pentamer(+) cell proliferation after specific in vitro challenge was impaired (P < 0.05), although this was corrected by z-VAD-fmk treatment (P < 0.05). Mcl-1 expression was low directly ex vivo (P < 0.01), and Bim was up-regulated after antigen encounter (P < 0.05) of CD127(low) pentamer(+) cells. The ex vivo difference between Mcl-1 and Bim expression on pentamer(+) cells correlated positively with CD127 expression level (P < 0.001) and with pentamer(+) cell reactivity (P < 0.05). In summary, a low ex vivo Mcl-1 expression and Bim up-regulation after antigen encounter are involved in CD127(low) HCV-specific CTL hyporeactivity during chronic infection, but it can be overcome by apoptosis blockade.
Asunto(s)
Proteínas Reguladoras de la Apoptosis/metabolismo , Hepacivirus/inmunología , Hepatitis C Crónica/inmunología , Subunidad alfa del Receptor de Interleucina-7/genética , Proteínas de la Membrana/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Linfocitos T Citotóxicos/fisiología , Adulto , Apoptosis , Proteína 11 Similar a Bcl2 , Proliferación Celular , Células Cultivadas , Estudios Transversales , Regulación hacia Abajo , Femenino , Hepacivirus/fisiología , Hepatitis C Crónica/metabolismo , Hepatitis C Crónica/virología , Interacciones Huésped-Patógeno , Humanos , Interferón gamma/metabolismo , Subunidad alfa del Receptor de Interleucina-7/metabolismo , Masculino , Persona de Mediana Edad , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Fenotipo , Linfocitos T Citotóxicos/virología , Replicación ViralAsunto(s)
Pancreatitis , Enfermedad Aguda , Humanos , Pancreatitis/diagnóstico , Pancreatitis/terapiaAsunto(s)
Humanos , Masculino , Femenino , Pancreatitis Aguda Necrotizante/diagnóstico , Pancreatitis Aguda Necrotizante/etiología , Pancreatitis Aguda Necrotizante/terapia , Cálculos de la Vejiga Urinaria/complicaciones , Cálculos de la Vejiga Urinaria/diagnóstico , Cálculos de la Vejiga Urinaria/terapia , Nutrición Parenteral Total/instrumentación , Nutrición Parenteral Total/métodos , Nutrición Parenteral Total/tendencias , Colangiopancreatografia Retrógrada Endoscópica/métodos , Pronóstico , Enfermedades Pancreáticas/diagnóstico , Enfermedades Pancreáticas/terapia , Páncreas/anatomía & histología , Páncreas/fisiología , Diagnóstico Precoz , Colangiopancreatografia Retrógrada Endoscópica/tendencias , Colecistectomía/tendencias , ColecistectomíaRESUMEN
Cytokines make up a network of molecules involved in the regulation of immune response and organ functional homeostasis. Cytokines coordinate both physiological and pathological processes occurring in the liver during viral infection, including infection control, inflammation, regeneration, and fibrosis. Hepatitis B and hepatitis C viruses interfere with the complex cytokine network brought about by the immune system and liver cells in order to prevent an effective immune response, capable of viral control. This situation leads to intrahepatic sequestration of nonspecific inflammatory infiltrates that release proinflammatory cytokines, which in turn favor chronic inflammation and fibrosis. The therapeutical administration of cytokines such as interferon alpha may result in viral clearance during persistent infection, and revert this process.
Asunto(s)
Antivirales/uso terapéutico , Citocinas/fisiología , Hepatitis B Crónica/fisiopatología , Hepatitis C Crónica/fisiopatología , Interferón-alfa/uso terapéutico , Antivirales/administración & dosificación , Antivirales/farmacología , Apoptosis/fisiología , Citocinas/metabolismo , Citocinas/farmacología , Quimioterapia Combinada , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/inmunología , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/inmunología , Hepatocitos/patología , Hepatocitos/virología , Humanos , Interferón-alfa/administración & dosificación , Interferón-alfa/fisiología , Hígado/inmunología , Hígado/metabolismo , Hígado/patología , Subgrupos Linfocitarios/inmunología , Modelos Biológicos , Receptores de Citocinas/fisiología , Ribavirina/administración & dosificación , Ribavirina/uso terapéutico , Replicación Viral/efectos de los fármacosRESUMEN
Cytokines make up a network of molecules involved in the regulationof immune response and organ functional homeostasis. Cytokinescoordinate both physiological and pathological processesoccurring in the liver during viral infection, including infection control,inflammation, regeneration, and fibrosis. Hepatitis B and hepatitisC viruses interfere with the complex cytokine networkbrought about by the immune system and liver cells in order to preventan effective immune response, capable of viral control. This situationleads to intrahepatic sequestration of nonspecific inflammatoryinfiltrates that release proinflammatory cytokines, which in turnfavor chronic inflammation and fibrosis. The therapeutical administrationof cytokines such as interferon alpha may result in viral clearanceduring persistent infection, and revert this process(AU)
Asunto(s)
Humanos , Masculino , Femenino , Antivirales/uso terapéutico , Citocinas/fisiología , Hepatocitos/patología , Hepatitis B Crónica/fisiopatología , Hepatitis C Crónica/fisiopatología , Interferones/uso terapéutico , Ribavirina/uso terapéutico , Antivirales/administración & dosificación , Apoptosis/fisiología , Citocinas , Quimioterapia Combinada , Hepatitis B Crónica/inmunología , Hepatitis C Crónica/inmunología , Hepatocitos/virología , Modelos Biológicos , Replicación ViralRESUMEN
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