Asunto(s)
Espasmo Hemifacial/diagnóstico por imagen , Síndromes de Compresión Nerviosa/diagnóstico , Adulto , Anticonvulsivantes/uso terapéutico , Colombia/etnología , Dibenzazepinas/uso terapéutico , Femenino , Gabapentina/uso terapéutico , Espasmo Hemifacial/tratamiento farmacológico , Humanos , Contracción Muscular , España , Vértigo/etiologíaRESUMEN
Foxp3(+) regulatory T cells in peripheral tissues (pT(regs)) are instrumental in limiting inflammatory responses to nonself antigens. Within the intestine, pT(regs) are located primarily in the lamina propria, whereas intraepithelial CD4(+) T cells (CD4(IELs)), which also exhibit anti-inflammatory properties and depend on similar environmental cues, reside in the epithelium. Using intravital microscopy, we show distinct cell dynamics of intestinal T(regs) and CD4(IELs) Upon migration to the epithelium, T(regs) lose Foxp3 and convert to CD4(IELs) in a microbiota-dependent manner, an effect attributed to the loss of the transcription factor ThPOK. Finally, we demonstrate that pT(regs) and CD4(IELs) perform complementary roles in the regulation of intestinal inflammation. These results reveal intratissue specialization of anti-inflammatory T cells shaped by discrete niches of the intestine.
Asunto(s)
Animales , Movimiento Celular , Rastreo Celular , Colitis , Factor Nuclear 3-gamma del Hepatocito , Mucosa Intestinal , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Microbiota , Linfocitos T Reguladores , Factores de TranscripciónRESUMEN
Enhancing repair of myelin is an important but still elusive therapeutic goal in many neurological disorders. In multiple sclerosis, an inflammatory demyelinating disease, endogenous remyelination does occur but is frequently insufficient to restore function. Both parenchymal oligodendrocyte progenitor cells and endogenous adult neural stem cells resident within the subventricular zone are known sources of remyelinating cells. Here we characterize the contribution to remyelination of a subset of adult neural stem cells, identified by their expression of Gli1, a transcriptional effector of the sonic hedgehog pathway. We show that these cells are recruited from the subventricular zone to populate demyelinated lesions in the forebrain but never enter healthy, white matter tracts. Unexpectedly, recruitment of this pool of neural stem cells, and their differentiation into oligodendrocytes, is significantly enhanced by genetic or pharmacological inhibition of Gli1. Importantly, complete inhibition of canonical hedgehog signalling was ineffective, indicating that the role of Gli1 both in augmenting hedgehog signalling and in retarding myelination is specialized. Indeed, inhibition of Gli1 improves the functional outcome in a relapsing/remitting model of experimental autoimmune encephalomyelitis and is neuroprotective. Thus, endogenous neural stem cells can be mobilized for the repair of demyelinated lesions by inhibiting Gli1, identifying a new therapeutic avenue for the treatment of demyelinating disorders.
Asunto(s)
Encefalomielitis Autoinmune Experimental/metabolismo , Factores de Transcripción de Tipo Kruppel/antagonistas & inhibidores , Vaina de Mielina/metabolismo , Células-Madre Neurales/citología , Células-Madre Neurales/fisiología , Sustancia Blanca/metabolismo , Sustancia Blanca/patología , Células Madre Adultas/citología , Células Madre Adultas/metabolismo , Animales , Diferenciación Celular , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/patología , Femenino , Proteínas Hedgehog/metabolismo , Factores de Transcripción de Tipo Kruppel/metabolismo , Ventrículos Laterales , Ratones , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/patología , Fármacos Neuroprotectores/antagonistas & inhibidores , Fármacos Neuroprotectores/metabolismo , Oligodendroglía/citología , Prosencéfalo/metabolismo , Prosencéfalo/patología , Transducción de Señal , Sustancia Blanca/citología , Proteína con Dedos de Zinc GLI1RESUMEN
Transplanted individuals in operational tolerance (OT) maintain long-term stable graft function after completely stopping immunosuppression. Understanding the mechanisms involved in OT can provide valuable information about pathways to human transplantation tolerance. Here we report that operationally tolerant individuals display quantitative and functional preservation of the B-cell compartment in renal transplantation. OT exhibited normal numbers of circulating total B cells, naive, memory and regulatory B cells (Bregs) as well as preserved B-cell receptor repertoire, similar to healthy individuals. In addition, OT also displayed conserved capacity to activate the cluster of differentiation 40 (CD40)/signal transducer and activator of transcription 3 (STAT3) signaling pathway in Bregs, in contrast, with chronic rejection. Rather than expansion or higher activation, we show that the preservation of the B-cell compartment favors OT.
Asunto(s)
Linfocitos B/inmunología , Trasplante de Riñón/inmunología , Tolerancia al Trasplante/inmunología , Adulto , Anciano , Linfocitos B/metabolismo , Linfocitos B Reguladores/inmunología , Linfocitos B Reguladores/metabolismo , Antígenos CD40/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Receptores de Antígenos de Linfocitos B/genética , Receptores de Antígenos de Linfocitos B/inmunología , Factor de Transcripción STAT3/metabolismo , Transducción de SeñalRESUMEN
Some organ-transplanted patients achieve a state of "operational tolerance" (OT) in which graft function is maintained after the complete withdrawal of immunosuppressive drugs. We used a gene panel of regulatory/inflammatory molecules (FOXP3, GATA3, IL10, TGFB1, TGFBR1/ TBX21, TNF and IFNG) to investigate the gene expression profile in peripheral blood mononuclear cells of renal-transplanted individuals experiencing OT compared to transplanted individuals not displaying OT and healthy individuals (HI). OT subjects showed a predominant regulatory (REG) profile with higher gene expression of GATA3, FOXP3, TGFB1 and TGFB receptor 1 compared to the other groups. This predominant REG gene expression profile displayed stability over time. The significant GATA3 gene and protein expressions in OT individuals suggest that a Th2 deviation may be a relevant pathway to OT. Moreover, the capacity of the REG/INFLAMMA gene panel to discriminate OT by peripheral blood analysis indicates that this state has systemic repercussions.
Asunto(s)
Factor de Transcripción GATA3 , Inmunosupresores/metabolismo , Trasplante de Riñón/inmunología , Leucocitos Mononucleares/fisiología , Tolerancia al Trasplante , Adulto , Anciano , Femenino , Factores de Transcripción Forkhead/sangre , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Factor de Transcripción GATA3/sangre , Factor de Transcripción GATA3/genética , Factor de Transcripción GATA3/metabolismo , Perfilación de la Expresión Génica , Supervivencia de Injerto/inmunología , Humanos , Inmunosupresores/sangre , Masculino , Persona de Mediana Edad , Receptores de Factores de Crecimiento Transformadores beta/sangre , Receptores de Factores de Crecimiento Transformadores beta/genética , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Estudios Retrospectivos , Células Th2/metabolismo , Factor de Crecimiento Transformador beta1/sangre , Factor de Crecimiento Transformador beta1/genética , Factor de Crecimiento Transformador beta1/metabolismo , Tolerancia al Trasplante/genética , Tolerancia al Trasplante/inmunologíaRESUMEN
In organ transplantation, the immunosuppression withdrawal leads, in most cases, to rejection. Nonetheless, a special group of patients maintain stable graft function after complete withdrawal of immunosuppression, achieving a state called "operational tolerance." The study of such patients may be important to understand the mechanisms involved in human transplantation tolerance. We compared the profile of CD4(+)CD25(+)Foxp3(+) T cells and the signaling pathways IL-6/STAT3 (signal transducers and activators of transcription) and IL-4/STAT6 in peripheral blood mononuclear cells of four kidney transplant groups: (i) operational tolerance (OT), (ii) chronic allograft nephropathy (CR), (iii) stable graft function under standard immunosuppression (Sta), (iv) stable graft function under low immunosuppression, and (v) healthy individuals. Both CR and Sta displayed lower numbers and percentages of CD4(+)CD25(+)Foxp3(+) T cells compared with all other groups (p < 0.05). The OT patients displayed a reduced activation of the IL-4/STAT6 pathway in monocytes, compared with all other groups (p < 0.05). The lower numbers of CD4(+)CD25(+)Foxp3(+) T cells observed in CR individuals may be a feature of chronic allograft nephropathy. The differential OT signaling profile, with reduced phosphorylation of STAT6, in monocytes' region, suggests that some altered function of STAT6 signaling may be important for the operational tolerance state.
Asunto(s)
Trasplante de Riñón/inmunología , Monocitos/inmunología , Factor de Transcripción STAT6/metabolismo , Linfocitos T Reguladores/inmunología , Tolerancia al Trasplante/inmunología , Adulto , Separación Celular , Femenino , Citometría de Flujo , Factores de Transcripción Forkhead , Rechazo de Injerto/inmunología , Rechazo de Injerto/prevención & control , Humanos , Inmunosupresores/uso terapéutico , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Monocitos/metabolismo , Receptores de Interleucina-4 , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/inmunología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Linfocitos T Reguladores/metabolismoRESUMEN
Strategies to minimize the immunogenicity and toxicity of murine anti-CD3 antibodies (e.g. OKT3) are of special interest for organ transplantation and for the treatment of autoimmune diseases. In the present work, we have developed two humanized anti-CD3 antibodies. These molecules were shown to bind to human CD3, though less efficiently, and display less mitogenic activity than OKT3. These results prompted us to investigate whether this reduced mitogenic potential was associated with the development of anti-inflammatory properties. Indeed, in peripheral blood mononuclear cells (PBMCs), the humanized antibody versions induced a predominantly anti-inflammatory cytokine profile, in contrast with the pro-inflammatory profile induced by OKT3. Neither OKT3 nor the humanized versions induced the expression of IL-4, IL-2 or TGF-beta. Both humanized antibodies induced significantly lower production of IFN-gamma and IL-5 and slightly higher production of IL-10 than OKT3. This immunomodulatory profile was most evident by the 80-fold higher ratio of IL-10/IFN-gamma production in PBMCs cultured in the presence of the humanized antibodies, compared to those stimulated with OKT3. Furthermore, these humanized anti-CD3 antibodies induced a late FOXP3 gene expression while OKT3 led to a more transient expression of FOXP3. Taken our results, we suggest that these humanized anti-CD3 antibodies may promote the development of T cells with immunoregulatory activity.