Multiple sclerosis (MS) can be divided into four clinical forms: relapsing-remitting (RR), primary progressive (PP), secondary progressive (SP) and progressive relapsing (PR). The pathogenesis of the progressive forms of MS remains unclear, partly due to the lack of animal models that have these clinical patterns of disease. Using an encephalitogenic peptide from myelin oligodendrocyte glycoprotein (MOG)92-106, we have established animal models that mimic the different forms of MS in two strains of MHC identical H-2s mice, SJL/J and A.SW. We induce experimental allergic encephalomyelitis (EAE) with (MOG)92-106 in the presence or absence of supplemental Bordetella pertussis (BP). SJL/J mice develop RR-EAE whether BP was administered or not. Interestingly, A.SW mice develop PP-EAE without BP and SP-EAE with BP supplementation. Histologically, SJL/J mice develop a mild demyelinating disease with extensive T cell infiltration, while A.SW mice develop large plaque-like demyelinating lesions with immunoglobulin deposition and neutrophil infiltration, associated with very minimal T cell infiltration. In A.SW mice without BP, high titer serum anti-MOG antibody is detected and the anti-MOG IgG2a/IgG1 ratio correlated with survival times of the mice. We hypothesize that, in A.SW mice, a Th2 response favors the production of myelinotoxic antibodies, leading to progressive forms of EAE with early death, while a Th1 response in SJL mice favors a RR form with longer survival. To test this hypothesis, four specific aims are proposed.
The first aim will study the role of NK1.1+ T cells in progressive disease.
The second aim will determine whether IL-4 is responsible for the T helper (Th) 2 phenotype and progressive EAE seen in A.SW mice sensitized with (MOG)92-106.
The third aim will be to investigate the role of anti-myelin antibodies in disease progression and contribution to lesion formation. The fourth and last aim will study other factors involved in progressive disease such as environmental and genetic contributions. These new models could help explain the transition from RR disease to progressive disease often observed in MS patients.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BDCN-4 (01))
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Utz, Ursula
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University of Utah
Schools of Medicine
Salt Lake City
United States
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Peterson, Lisa K; Tsunoda, Ikuo; Libbey, Jane E et al. (2008) Role of B:T cell ratio in suppression of clinical signs: a model for silent MS. Exp Mol Pathol 85:28-39
Peterson, Lisa K; Tsunoda, Ikuo; Fujinami, Robert S (2008) Role of CD5+ B-1 cells in EAE pathogenesis. Autoimmunity 41:353-62
Peterson, Lisa K; Masaki, Takahisa; Wheelwright, Steven R et al. (2008) Cross-reactive myelin antibody induces renal pathology. Autoimmunity 41:526-36
Peterson, Lisa K; Fujinami, Robert S (2007) Inflammation, demyelination, neurodegeneration and neuroprotection in the pathogenesis of multiple sclerosis. J Neuroimmunol 184:37-44
Peterson, Lisa K; Tsunoda, Ikuo; Masaki, Takahisa et al. (2007) Polyreactive myelin oligodendrocyte glycoprotein antibodies: Implications for systemic autoimmunity in progressive experimental autoimmune encephalomyelitis. J Neuroimmunol 183:69-80
Welsh, Raymond M; Fujinami, Robert S (2007) Pathogenic epitopes, heterologous immunity and vaccine design. Nat Rev Microbiol 5:555-63
Tsunoda, Ikuo; Terry, Emily Jane; Marble, Benjamin J et al. (2007) Modulation of experimental autoimmune encephalomyelitis by VLA-2 blockade. Brain Pathol 17:45-55
Libbey, Jane E; Peterson, Lisa K; Tsunoda, Ikuo et al. (2006) Monoclonal MOG-reactive autoantibody from progressive EAE has the characteristics of a natural antibody. J Neuroimmunol 173:135-45
Tsunoda, Ikuo; Libbey, Jane E; Kuang, Li-Qing et al. (2005) Massive apoptosis in lymphoid organs in animal models for primary and secondary progressive multiple sclerosis. Am J Pathol 167:1631-46
Tsunoda, Ikuo; Kuang, Li-Qing; Igenge, Isaac Z M et al. (2005) Converting relapsing remitting to secondary progressive experimental allergic encephalomyelitis (EAE) by ultraviolet B irradiation. J Neuroimmunol 160:122-34