RESUMEN
There is much interest in therapeutic manipulation of cytokine responses in autoimmunity, yet studies in mouse models have sometimes produced conflicting findings as to the role of particular mediators in disease. Examples include the contradictory findings regarding susceptibility to experimental allergic encephalomyelitis (EAE) or diabetes in knockout mice for various individual Th1 or Th2 cytokines or their receptors. An alternative approach to the analysis of Th1 and Th2 mechanisms in these diseases is to investigate strains carrying a null mutation for molecules involved in cytokine receptor signal transduction, signal transducer and activator of transcription (Stat4) and Stat6. Stat4 is pivotal in Th1 polarization, being activated when IL-12 binds the IL-12R and leading to the production of IFNgamma. We here report disease susceptibility in non-obese diabetic mice carrying a Stat4-null mutation. Knockout mice were almost completely protected from diabetes, only rarely showing pancreatic peri-islet infiltrates. Furthermore, there was near complete protection from the induction of EAE by either of the two encephalitogenic myelin epitopes. Despite this protection, Stat4-null mice showed clear epitope spread compared with controls during myelin oligodendrocyte glycoprotein-induced EAE as judged by T cell proliferation, although this was not associated with a strong Th1 response to the initial or spread epitope and, furthermore, there was no evidence of a switch to Th2 cytokines.
Asunto(s)
Diabetes Mellitus/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Epítopos de Linfocito T/inmunología , Vaina de Mielina/inmunología , Factor de Transcripción STAT4/inmunología , Células TH1/inmunología , Animales , Proliferación Celular , Citocinas/inmunología , Diabetes Mellitus/genética , Encefalomielitis Autoinmune Experimental/genética , Ratones , Ratones Endogámicos NOD , Ratones Noqueados , Factor de Transcripción STAT4/genética , Transducción de Señal/inmunologíaRESUMEN
Acute lymphoblastic leukaemia (ALL) is the commonest form of childhood malignancy, and most cases arise from B-cell clones arrested at the pre-B-cell stage of differentiation. The molecular events that arrest pre-B-cell differentiation in the leukaemic pre-B cells have not been well characterized. Here we show that the differentiation regulator SLP-65 (an adaptor protein also called BLNK or BASH) inhibits pre-B-cell leukaemia in mice. Reconstitution of SLP-65 expression in a SLP-65-/- pre-B-cell line led to enhanced differentiation in vitro and prevented the development of pre-B-cell leukaemia in immune-deficient mice. Tyrosine 96 of SLP-65 was required for this activity. The murine SLP-65-/- pre-B-cell leukaemia resembles human childhood pre-B ALL. Indeed, 16 of the 34 childhood pre-B ALL samples that were tested showed a complete loss or drastic reduction of SLP-65 expression. This loss is probably due to the incorporation of alternative exons into SLP-65 transcripts, leading to premature stop codons. Thus, the somatic loss of SLP-65 and the accompanying block in pre-B-cell differentiation might be one of the primary causes of childhood pre-B ALL.
Asunto(s)
Proteínas Portadoras/metabolismo , Fosfoproteínas/deficiencia , Fosfoproteínas/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Adolescente , Adulto , Agammaglobulinemia Tirosina Quinasa , Animales , Linfocitos B/metabolismo , Secuencia de Bases , Sitios de Unión , Proteínas Portadoras/genética , Diferenciación Celular , División Celular , Células Cultivadas , Niño , Preescolar , Exones/genética , Eliminación de Gen , Regulación Neoplásica de la Expresión Génica , Humanos , Lactante , Ratones , Ratones Noqueados , Mutación , Fosfoproteínas/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Proteínas Tirosina Quinasas/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Bazo/patologíaRESUMEN
As células endoteliais, além de serem elementos relevantes na hemostasia e manutençäo do tônus vascular, ocupam papel importante na resposta imune.Embora näo sejam consideradas células apresentadoras de antígeno (APC) profissionais, as células endoteliais expressamambos os antígeno MHC de classe I (constitutivamente)e classe II (algumas constitutivamente, outras somente após ativaçäo).Também apresentam diversas moléculasde adesäo, algumas das quais atuam como importantes sinais co-estimulatórios para ativaçäode linfócitos.Além disso secretam diferentes citocinas e fatores de crescimento que podem atuar de maneira autócrinica ou parácrina, modulando importantes funçöes de linfócitos, monócitos e células muswculares lisas.Embora näo haja consenso na literatura, dados de diferentes grupos têm demonstrado que as células endoteliais podem apresentar antígenos, como fornecer sinais co-estimulatórios para os linfócitos, desencadeando resposta proliferativa e citotóxica, ou ainda, indiretamente, resposta humoral.Um dos mais intrigantes e debatidos papéis da célula endotelial é no alotransplante. A participaçäo das células endoteliais vasculares, como alvo ou como agente ativo do processo de rejeiçäo,é ainda discutida.Muitos estudos têm descrito que a célula endotelial pode induzir a resposta alogênica de células T em repouso.Dados de nosso laboratório e de outros têm demonstrado que a resposta a supostos antígenos endotélio-específicos tem sido associada com a perda do enxerto no transplante humano.Recentemente, mais atençäo tem sido dada ao papel da células endotelial na patogênese da doença vascular do exerto (aterosclerose do enxerto).Esses vários aspectos das funçöes da célula endotelial na resposta imune seräo abordados.