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1.
Dig Dis ; 30(4): 392-5, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22796803

RESUMEN

Immune function in the gut mucosa is tightly regulated to prevent deleterious tissue damaging responses to the indigenous microbiota. In animal models, negative regulatory molecules such as transforming growth factor ß1 (TGFß1) and interleukin (IL)-10 seem to be particularly important. Although IL-10 is made by macrophages, T cells and B cells, TGFß1 is made by many non-lymphoid/myeloid cells, especially epithelial cells. We have been able to show that in the human gut, neutralization of TGFß1 increases Th1 and Th17 responses. In IBD, however, especially Crohn's disease, exogenous TGFß1 cannot inhibit inflammation because of a block in intracellular signalling mediated by Smad7. Knockdown of Smad7 allows endogenous TGFß1 to dampen inflammation in mucosal tissues from Crohn's patients. We have also generated a mouse which over-expresses Smad7 in T cells. This animal develops more severe colitis in a number of different models, but the inflammation helps protect against colon cancer.


Asunto(s)
Sistema Inmunológico/inmunología , Enfermedades Inflamatorias del Intestino/inmunología , Animales , Humanos , Enfermedades Inflamatorias del Intestino/metabolismo , Interleucina-10/metabolismo , Proteína smad7/metabolismo , Linfocitos T/inmunología , Factor de Crecimiento Transformador beta1/metabolismo
2.
Gastroenterology ; 133(4): 1175-87, 2007 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-17919493

RESUMEN

BACKGROUND & AIMS: Dendritic cells (DCs) play a crucial role in immune responses by controlling the extent and type of T-cell response to antigen. Celiac disease is a condition in which T-cell immunity to gluten plays an important pathogenic role, yet information on DCs is scant. We examined mucosal DCs in celiac disease in terms of phenotype, activation/maturation state, cytokine production, and function. METHODS: Mucosal DCs from 48 celiacs and 30 controls were investigated by flow cytometry. In situ distribution of DCs was analyzed by confocal microscopy. Interferon (IFN)-alfa, interleukin (IL)-4, IL-5, IL-12p35, IL-12p40, IL-18, IL-23p19, IL-27, and transforming growth factor-beta transcripts were measured by real-time reverse-transcription polymerase chain reaction in sorted DCs. DC expression of IL-6, IL-12p40, and IL-10 was assessed by intracellular cytokine staining. The effect of IFN-alfa and IL-18 blockade on the gluten-induced IFN-gamma response in celiac biopsy specimens grown ex vivo also was investigated. RESULTS: Mucosal DCs were increased in untreated, but not treated, celiacs. The majority of them were plasmacytoid with higher levels of maturation (CD83) and activation (CD80/CD86) markers. Higher transcripts of Th1 relevant cytokines, such as IFN-alfa, IL-18, and IL-23p19, were produced by celiac DCs, but because IL-12p40 was undetectable, a role for IL-23 is unlikely. Intracellular cytokine staining of celiac DCs showed higher IL-6, but lower IL-10 expression, and confirmed the lack of IL-12p40. Blocking IFN-alfa inhibited IFN-gamma transcripts in ex vivo organ culture of celiac biopsy specimens challenged with gluten. CONCLUSIONS: These data suggest that IFN-alfa-producing DCs contribute to the Th1 response in celiac disease.


Asunto(s)
Enfermedad Celíaca/metabolismo , Células Dendríticas/metabolismo , Glútenes/inmunología , Inmunidad Celular , Inmunidad Mucosa , Interferón-alfa/metabolismo , Mucosa Intestinal/metabolismo , Células TH1/metabolismo , Anticuerpos , Antígenos CD/análisis , Estudios de Casos y Controles , Enfermedad Celíaca/dietoterapia , Enfermedad Celíaca/genética , Enfermedad Celíaca/inmunología , Diferenciación Celular , Separación Celular , Células Cultivadas , Ciclooxigenasa 2/análisis , Células Dendríticas/inmunología , Dieta con Restricción de Proteínas , Citometría de Flujo , Gliadina/inmunología , Humanos , Interferón-alfa/genética , Interferón-alfa/inmunología , Interferón gamma/genética , Interferón gamma/metabolismo , Interleucinas/genética , Interleucinas/metabolismo , Mucosa Intestinal/enzimología , Mucosa Intestinal/inmunología , Microscopía Confocal , Fragmentos de Péptidos/inmunología , Fenotipo , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células TH1/inmunología , Técnicas de Cultivo de Tejidos , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismo
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