Multiple sclerosis (MS) is a neuroinflammatory disease of the central nervous system. The diverse clinical signs seen in MS patients reflect the wide distribution of inflammatory infiltrates, demyelinating plaques and axonal damage in the white matter tracks of the brain and spinal cord. Experimental allergic encephalomyelitis (EAE) is an animal model of MS that is induced by stimulating T cell-mediated immunity to myelin antigens. EAE has many similarities to MS, including the presence of inflammatory infiltrates and demyelination in the white matter. Unlike MS, however, the lesions are restricted predominantly to the spinal cord with significantly less inflammation seen in the brain. Thus, most rodent EAE models are not amenable to investigate mechanisms for targeting inflammation to the brain as well as the spinal cord. We have developed a unique model of EAE that allows us to determine the basis for different patterns of inflammation in the CNS. C3HeB/Fej x C3H.SW F1 mice generate T cells specific for three epitopes of myelin oligodendrocyte glycoprotein (MOG): MOG97-114, MOG79-90 and MOG35-55. Adoptive transfer of MOG97-114-specific T cells induces inflammation predominantly in the brain and not the spinal cord, while transfer of MOG79-90 and MOG35-55-specific T cells induces inflammation localized in the spinal cord and not the brain. T cells specific for all three epitopes generate IL-17+ and IFN-3+ cells, however, the IL-17:IFN-3 ratio is significantly higher for MOG97-114-specific T cells. By manipulating Th17:Th1 ratios for each specificity, we demonstrate that the localization of inflammatory cells in the brain versus the spinal cord is regulated by the ratio, and not the absolute number or epitope specificity, of myelin-specific Th17 and Th1 cells. Interestingly, MOG97-114 specific T cells also exhibit a higher functional avidity for their antigen compared to either MOG79-90 or MOG35-55-specific T cells. We propose to test the hypotheses that 1) T cell functional avidity for antigen determines the Th17:Th1 ratio in the responding population, 2) Th17 and Th1 cells differ in their ability to either migrate to, survive in, and/or proliferate in the brain versus the spinal cord and 3) resident cells within the brain and spinal cord differ in their response to infiltrating T cell populations biased toward Th17 or Th1.Project Narrative In multiple sclerosis, inflammatory lesions are typically disseminated in the white matter of the brain and frequently the spinal cord;however, lesions in most rodent models of MS predominate in the spinal cord with little brain inflammation. We developed a unique mouse model in which mechanisms mediated by different types of pathogenic T cells will be defined that regulates brain versus spinal cord inflammation. A better understanding of how, where and why different T cell subsets initiate and sustain inflammation in the central nervous system is critical to predict the efficacy and consequences of manipulating the activity of these T cells in MS therapies.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
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Esch, Thomas R
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University of Washington
Schools of Medicine
United States
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Simmons, Sarah B; Pierson, Emily R; Lee, Sarah Y et al. (2013) Modeling the heterogeneity of multiple sclerosis in animals. Trends Immunol 34:410-22
Goverman, Joan M (2011) Immune tolerance in multiple sclerosis. Immunol Rev 241:228-40
Goverman, Joan (2009) Autoimmune T cell responses in the central nervous system. Nat Rev Immunol 9:393-407