Multiple sclerosis : MRI diagnosis, potential treatment and future potential for nanoparticle applications

Abstract: Multiple Sclerosis is an inflammatory demyelinating and neurodegenerative disease of the central nervous system. Magnetic resonance imaging is an important tool for diagnosing of Multiple Sclerosis and for, in vivo, monitoring its evolution of pathology. The introduction of interferon (IFN)-beta therapy has altered the natural course of Multiple Sclerosis. We investigated the effect of low-dose low-frequency and high-dose highfrequency IFNbeta- 1a treatment in patients with secondary progressive Multiple Sclerosis, and also after discontinuation of treatment by volumetric magnetic resonance imaging and clinical assessments. The longitudinal study showed that a single weekly dose of 22 µg IFN-beta-1a had a mild beneficial effect as visualized by magnetic resonance imaging, but this dosage and frequency of administration was insufficient in controlling clinical disease activity. Discontinuation of IFN-beta1a was associated with an acceleration of neurological disability and progression of brain lesion. A major hurdle in the research of neuroinflammatory disorders of the central nervous system is the inaccessibility of the organ. To overcome such limitations development of relevant animal models has been an important approach. Experimental autoimmune/or allergic encephalomyelitis (EAE) is an animal model that closely mimics key features of human Multiple Sclerosis. We studied EAE-regulatory genes and explored novel individualized therapeutic strategies in EAE models. Genetic factors play an important role in the expression of the disease, also shown experimentally in a number of inbred rat strains that differ in their relative susceptibilities to EAE. The availability of such strains of rats, the discovery of polymorphic genetic markers, as well as the development of genetic and physical maps provided an opportunity for mapping of diseaseregulating genes in EAE. We fine-mapped quantitative trait loci (QTL) that regulate EAE on rat chromosome 10 in the 7th generation of an advanced intercross line (AIL). AIL mapping was proved to be an efficient approach to narrow down QTL and to resolve closely situated QTL. Dendritic cells (DC) not only control immunity, but also maintain tolerance to self-antigens, thereby minimizing autoaggressive immune responses. We investigated the therapeutic potential of IFN-gamma modified DC and CD8alpha+ DC, respectively, in rat and mouse EAE models. The severity of the disease was dramatically inhibited in animals injected with IFN-gamma modified DC or CD8alpha+ DC evaluated clinically and by magnetic resonance imaging. In conclusion, in my thesis I have studied Multiple Sclerosis from clinical and experimental perspective, genetic pathogenesis into therapeutic strategies using magnetic resonance imaging and EAE animal models as tools.