RESUMO
Biozzi ABH mice develop a reproducible, relapsing-remitting form of experimental autoimmune encephalomyelitis (EAE) that becomes secondary progressive with disease duration. The relapses observed are T-cell dependent and can be inhibited by immune tolerance induction. In contrast the progressive neurodegeneration is T cell-independent and continues despite the re-induction of immune tolerance. Here we present a practical guide to EAE induction in the ABH mouse and approaches used to control relapses such that both autoimmune-independent and autoimmune-dependent mechanisms of neurodegeneration can be explored. Disease-related weight changes are associated with blood-brain barrier dysfunction and clinical disease. A new method for detecting neurodegeneration is described along with new experimental details that will aid in the undertaking of studies in EAE in mice, with particularly emphasis on ABH mice.
RESUMO
Emerging autoimmunity (epitope-spreading) generated as a consequence of myelin damage is suggested to underlie the relapses in multiple sclerosis (MS). Myelin oligodendrocyte glycoprotein (MOG 8-21) induces relapsing EAE in ABH mice characterized by broadening of the autoimmune reportoire. Despite epitope spreading tolerance to the priming antigen, but not emerging epitope reactivities, resulted in long-term inhibition of clinical relapse. In contrast, spinal cord homogenate induced EAE was dominated by a proteolipid protein (PLP 56-70) autoreactivity despite the plethora of CNS antigens in the immunogen. This data suggests that during relapsing-remitting demyelinating disease the pathogenic process is dominated by the initiating antigen, with only a minor role played by emerging T-cell populations. These findings may have important implications for the efficacy of antigen-based immune therapies in autoimmune disorders.
Assuntos
Encefalomielite Autoimune Experimental/induzido quimicamente , Epitopos/imunologia , Glicoproteína Associada a Mielina/toxicidade , Linfócitos T/fisiologia , Animais , Apoproteínas/toxicidade , Proliferação de Células/efeitos dos fármacos , Citocinas/metabolismo , Progressão da Doença , Encefalomielite Autoimune Experimental/patologia , Ensaio de Imunoadsorção Enzimática/métodos , Epitopos/metabolismo , Ativação Linfocitária , Camundongos , Camundongos Biozzi , Camundongos Endogâmicos C57BL , Proteínas da Mielina , Proteína Proteolipídica de Mielina/toxicidade , Glicoproteína Mielina-Oligodendrócito , Fragmentos de Peptídeos/toxicidade , Recidiva , Estatísticas não Paramétricas , Linfócitos T/efeitos dos fármacos , Fatores de TempoRESUMO
To date there has been poor translation of immunotherapies from rodent models to treatment of progressive multiple sclerosis (MS). In the robust, relapsing Biozzi ABH mouse model of MS, using a combination of a transient deletion of T cells followed by intravenous (i.v.) myelin antigen administration, established relapsing disease in EAE can be effectively silenced. However, when treatment was initiated in late stage chronic-relapsing disease, despite inhibition of further relapses, mice demonstrated evidence of disease progression shown by a deterioration in mobility and development of spasticity and indicates that targeting relapsing, immunological components of MS alone is unlikely to be sufficient to control progression in the late stages of MS.