RESUMEN
In experimental autoimmune encephalomyelitis (EAE), CD4(+) self-reactive T cells target myelin components of the CNS. However, the consequences of an autoaggressive T cell response against myelin for neurons are currently unknown. We herein demonstrate that EAE induced by active immunization with an encephalitogenic myelin basic protein peptide dramatically reduces the loss of spinal motoneurons after ventral root avulsion in rats. Both brain-derived neurotophic factor (BDNF)- and neurotrophin-3 (NT-3)-like immunoreactivities were detected in mainly T and natural killer (NK) cells in the spinal cord. In addition, very high levels of BDNF, NT-3, and glial cell line-derived neurotrophic factor mRNAs were present in T and NK cell populations infiltrating the CNS. Interestingly, bystander recruited NK and T cells displayed similar or higher neurotrophic factor levels compared with the EAE disease-driving encephalitogenic T cell population. High levels of tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) mRNAs were also detected, and both these cytokines can be harmful to several types of CNS cells, including neurons. However, treatment of embryonic motoneuron cultures with TNF-alpha or IFN-gamma only had a deleterious effect in cultures deprived of neurotrophic factors. These results suggest that the potentially neurodamaging consequences of severe CNS inflammation are curbed by the production of several potent neurotrophic factors in leukocytes.
Asunto(s)
Encefalomielitis Autoinmune Experimental/metabolismo , Células Asesinas Naturales/metabolismo , Neuronas Motoras/efectos de los fármacos , Factores de Crecimiento Nervioso/biosíntesis , Linfocitos T/metabolismo , Animales , Supervivencia Celular/inmunología , Células Cultivadas , Sistema Nervioso Central/metabolismo , Citoprotección/inmunología , Relación Dosis-Respuesta a Droga , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/patología , Citometría de Flujo , Inmunohistoquímica , Interferón gamma/biosíntesis , Interferón gamma/farmacología , Células Asesinas Naturales/citología , Células Asesinas Naturales/inmunología , Ganglios Linfáticos/metabolismo , Microglía/efectos de los fármacos , Microglía/metabolismo , Neuronas Motoras/citología , Radiculopatía/inmunología , Ratas , Ratas Endogámicas Lew , Raíces Nerviosas Espinales/cirugía , Linfocitos T/citología , Linfocitos T/inmunología , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
DNA vaccines that encode encephalitogenic sequences in tandem can protect from subsequent experimental autoimmune encephalomyelitis induced with the corresponding peptide. The mechanism for this protection and, in particular, if it is specific for the amino acid sequence encoding the vaccine are not known. We show here that a single amino acid exchange in position 79 from serine (nonself) to threonine (self) in myelin basic protein peptide MBP68-85, which is a major encephalitogenic determinant for Lewis rats, dramatically alters the protection. Moreover, vaccines encoding the encephalitogenic sequence MBP68-85 do not protect against the second encephalitogenic sequence MBP89-101 in Lewis rats and vice versa. Thus, protective immunity conferred by DNA vaccination exquisitely discriminates between peptide target autoantigens. No bystander suppression was observed. The exact underlying mechanisms remain elusive because no simple correlation between impact on ex vivo responses and protection against disease were noted.