Studies of cellular pathogenesis in experimental autoimmune encephalomyelitis

Sammanfattning: In this thesis, I have studied antigen-specific therapeutic interventions of experimental autoimmune encephalomyelitis (EAE) and aimed to understand the respective roles of different cell subsets in initiation and perpetuation of disease. EAE is a commonly used animal model for the human disease Multiple Sclerosis (MS), a demyelinating disease mainly affecting young adults. The disease etiology is thought to be of autoimmune origin, where immunological attacks and subsequent destruction of myelin sheaths surrounding neurons result in neurological deficiencies and muscle paralysis. The molecular cause of initiation and progression of MS is still not clearly understood, despite extensive studies. In order to understand and develop measures to alleviate the effects of neurological deficiencies occurring in MS, EAE is induced by immunisation of myelin antigens in rodents that develop an MS-like disease with gradual progressive paralysis and myelin breakdown. Previous studies have established that the disease is mainly driven by T cells producing pro-inflammatory cytokines. Additional cell types work in an intriguing network in which they support each other to enact autoaggression. Therapeutic interventions are likely to affect the whole network, and thus it is important to understand the interaction and communication between these different cell types. The role of CD8+ T cells in perpetuating EAE was studied using genetically modified mice, and CD8+ T cells were determined to have an integral part in pathogenesis being linked with demyelination. In order to explore disease inducing and prevention mechanisms we employed antigen-specific interventions in EAE. Therapeutic administration of either protein antigen in adjuvant as well as DNA vaccine encoding antigen were both proven to be efficient in suppressing disease development. The protective mechanisms were long-lived, lacked shifts from a pathogenic type 1 cytokine response towards a proposed protective type 2 cytokine biased response, and were characterised by the survival of antigen-specific T cells. Further investigations of DNA vaccine-mediated protection revealed IFNbeta as being associated with disease suppression. The cell type hypothesised to be responsible for inducing protective immunity rather than pathology was plasmacytoid Dendritic cells (pDCs). We revealed a potential protective role of pDCs in EAE possibly due to induced IFNbeta production. This is consistent with the current use of IFNbeta in MS therapy where IFNbeta reduces relapse frequency via unknown mechanisms. Our studies might prove helpful in further characterising the role of pDCs and IFNbeta in EAE and MS.