The Animal Models Unit has employed a murine model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), to focus on the mechanisms driving pathogenic autoreactivity and triggers of autoimmunity in the CNS as well as investigating new modalities to treat disease that could be extended to therapies in MS. ? The study of humanized transgenic mice as a model of T cell receptor/ antigen/MHC interactions relevant to autoimmunity within the CNS is one focus of the group. We have wrapped up the characterization of two strains of transgenic mice carrying myelin reactive TCRs, and shown that the strain with the higher expression of MHC class II molecules can spontaneously develop autoimmunity at a low rate, serving as one of only a handful of models of spontaneous autoimmunity currently available. Further investigations within these models have shown that substituting the cognate antigen with a more stimulatory peptide allows for greater disease development irrespective of factors such as autoreactive T cell precursor frequency. Moreover, proteins within several human pathogens have been identified with homology to these stimulatory autoantigens, and serve as molecular mimics of the autoantigens in stimulating autoreactive T cells and driving the process of autoimmunity in these mice. ? The second focus of studies has been the investigation into new therapeutic approaches to treat autoimmune demyelination in the CNS using EAE. The first approach targets a reduction in the inflammatory component of the disease. In collaboration with John Hallenbeck of the Stroke Branch, NINDS, we have thus far shown that intranasal administration of the human cell adhesion molecule E selectin results in a tolerization process to this molecule. In the active induction model of EAE, E selectin tolerization pretreatment can reduce the incidence and severity of clinical symptoms once disease is induced. Moreover, preliminary studies also show a reduction in the severity of disease when E selectin is administered once disease has been established, emphasizing the therapeutic potential of this approach. Studies to identify the tolerogenic populations generated and their mechanisms of action in this model are ongoing. A patent application for this work is being finalized. A second study in collaboration with James Mitchell, NCI has been investigating the potential for a well characterized anti-oxidant to prevent or treat autoimmune demyelination in the EAE model, and thus far shows the ability to reduce the severity of clinical disease by two thirds when animals are maintained on the antioxidant diet.
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