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Show THE UNIVERSITY OF UTAH HEALTH SCIENCES LEAP PROGRAM TESTING THE EFFICACY OF DISEASE INDUCTION IN A "HUMANIZED" MURINE MODEL OF MULTIPLE SCLEROSIS Camilla Silva (Robert Fujinami) Department of Pathology University of Utah Multiple sclerosis (MS) is the most c o m m o n disease of the central nervous system in young adults. The most common animal model used to investigate the role of the immune system in neuroinflammation and demyelination, as well as to test the efficacy of new therapies for MS, is the experimental autoimmune encephalomyelitis (EAE) model. Mouse models of EAE are Tcell mediated. The sensitization and the presentation of myelin peptide lead to the activation of CD4+ T cells, which induces an inflammatory response, resulting in encephalomyelitis and demyelination. Unfortunately, the EAE murine model does not fully recapitulate key clinical features of MS, including primary and secondary progressive forms of the disease. In the Caucasian population, HLA-DRB1*1501 (DR-15) is the susceptibility gene for MS. DR-15- tg mice, a heterogeneous transgenic mouse model that is mouse major histocompatibility complex (MHC) class ll-deficient and human HLA-DRB1*1501-positive (DR-15-tg), and exhibits the strongest human genetic association with MS, have been created and are believed to be susceptible to EAE induced through sensitization with foreign myelin oligodendrocyte glycoprotein (MOG) peptides. Experimentally, w e evaluated whether human, rat, or mouse M O G could sensitize DR-15-tg mice to EAE. While all three species of M O G were able to induce EAE, mouse M O G exhibited the greatest ability to induce EAE with the highest histological scores in comparison to rat M O G , human M O G and the control group. Furthermore, DR-15-tg mice also presented with all M S clinical courses as seen in humans. In addition, T cells were detected in the spinal cords of MOG-sensitized mice by immunohistochemistry. In conclusion, DR-15-tg mice are susceptible to the induction of EAE through sensitization with human, rat, or mouse MOG, with mouse M O G creating the most effective EAE response. Therefore, we have developed a "humanized" murine model to study M S pathogenesis that closely models the clinical courses observed in humans. Robert Fujinami 169 |