RESUMEN
The expression of neural regulatory molecules by immune cells that infiltrate the nervous system upon injury may be a mechanism for cross-regulation between the nervous system and the immune system. Several lines of evidence implicate nerve growth factor (NGF) signaling through its receptors (TrkA and p75(NGFR)) as a potential source of communication between the two systems. We observed changes in NGF mRNA expression and protein secretion by T lymphocytes polarized toward the Th2 phenotype. The presence of NGF did not affect T cell proliferation or cytokine production in vitro. Mice treated with NGF by i. p. injection following induction of experimental autoimmune encephalomyelitis, an inflammatory, demyelinating disease of the central nervous system, showed a delayed onset of disease and lower clinical scores during the course of disease. These data suggest a role for NGF signaling in the regulation of the immune response, possibly by enhancing sympathetic innervation of lymphoid tissues.
Asunto(s)
Encefalomielitis Autoinmune Experimental/etiología , Factor de Crecimiento Nervioso/fisiología , Animales , Citocinas/biosíntesis , Encefalomielitis Autoinmune Experimental/inmunología , Interleucina-4/farmacología , Activación de Linfocitos , Linfocitos/metabolismo , Ratones , Ratones Transgénicos , Factor de Crecimiento Nervioso/genética , ARN Mensajero/análisisRESUMEN
Given the critical role of cytokines in the regulation of an inflammatory response, we investigated whether certain cytokines are expressed in the brains of normal mice during maturation that could contribute to the immune-privileged nature of the CNS or potentially influence an immune-mediated illness such as experimental allergic encephalomyelitis. The gene expression of IFN gamma (Th1 cytokine) and IL-4 (Th2 cytokine) was analyzed in the brain of several strains of mice. IFN gamma was not detectable. However, IL-4 was present in the brains of neonatal mice, but not adult mice. Resident CNS cells are believed to be the source of the IL-4, because mice deficient in T cells (SCID and RAG2-/-) expressed the IL-4 gene in the CNS. Further analysis indicated that the gene expression of the Th2 cytokine transcription factor, GATA-3, correlated with IL-4 and IL-10 expression in the brain. Since GATA-3-deficient mice have an abnormal CNS, brain-derived Th2 cytokines may play an important role in CNS development, as well as potentially contribute to the immune-privileged nature of the brain.
Asunto(s)
Química Encefálica/genética , Química Encefálica/inmunología , Regulación del Desarrollo de la Expresión Génica/inmunología , Interleucina-4/genética , Factores de Edad , Animales , Animales Recién Nacidos , Encéfalo/crecimiento & desarrollo , Encéfalo/inmunología , Cartilla de ADN , Proteínas de Unión al ADN/genética , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/inmunología , Factor de Transcripción GATA3 , Interferón gamma/genética , Interleucina-10/genética , Ratones , Ratones Endogámicos , Linfocitos T/inmunología , Transactivadores/genéticaRESUMEN
Recent evidence suggests that co-stimulation provided by B7 molecules through CTLA-4 is important in establishing peripheral tolerance. In the present study, we examined the kinetics of tolerance induction and T cell differentiation following i.p. administration of myelin basic protein (MBP) Ac1-11 in mice transgenic for a TCR V(beta)8.2 gene derived from an encephalitogenic T cell clone specific for MBP Ac1-11. Examination of the lymph node cell response after antigen administration demonstrated a dependence on CTLA-4 for i.p. tolerance induction. Examination of splenocyte responses suggested that i.p. antigen administration induced a T(h)2 response, which was potentiated by anti-CTLA-4 administration. Interestingly, i.p. tolerance was able to inhibit the induction of experimental autoimmune encephalomyelitis and anti-CTLA-4 administration did not alter this phenotype, suggesting that CTLA-4 blockade did not block tolerance induction. Thus, T cell differentiation and the dependence on CTLA-4 for tolerance induction following i.p. antigen administration differs between lymph node and spleen in a model of organ-specific autoimmunity.
Asunto(s)
Encefalomielitis Autoinmune Experimental/inmunología , Tolerancia Inmunológica , Inmunoconjugados , Proteína Básica de Mielina/administración & dosificación , Linfocitos T/fisiología , Abatacept , Animales , Antígenos CD , Antígenos de Diferenciación/fisiología , Antígeno CTLA-4 , Diferenciación Celular , Citocinas/biosíntesis , Inyecciones Intraperitoneales , Ratones , Ratones Transgénicos , Proteína Básica de Mielina/inmunología , Ovalbúmina/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/fisiologíaRESUMEN
Interactions between B7 molecules on antigen-presenting cells and CTLA-4 on T cells have been shown to be important in establishing tolerance. In the present study, we examined the kinetics of tolerance induction following i.v. administration of myelin basic protein (MBP) Ac1-11 in mice transgenic for a TCR V(beta)8.2 gene derived from an encephalitogenic T cell clone specific for MBP Ac1-11. Examination of the lymph node cell (LNC) response 10 days after antigen administration demonstrated an accentuation of i.v. tolerance induction with anti-CTLA-4 blockade. Anergy was induced in splenocytes by i.v. antigen administration as shown by a decrease in MBP-specific proliferation and IL-2 production, and anti-CTLA-4 potentiated this effect. In addition, i.v. antigen plus anti-CTLA-4 and complete Freund's adjuvant was not encephalitogenic. Interestingly, i.v. tolerance (a single injection) did not inhibit experimental autoimmune encephalomyelitis (EAE) and anti-CTLA-4 administration did not alter this phenotype. These results suggest that while the majority of MBP-specific T cells are tolerized by i.v. antigen and that this process is potentiated by anti-CTLA-4 administration, a population of T cells remains that is quite efficient in mediating EAE.