The goal of this project is to investigate the nature and specificity of the immune response that protects resistance mice from Theiler's murine encephalomyelitis virus (TMEV) persistent infection but which may also contribute in susceptible mice to demyelination and neurologic deficits. In this murine model of multiple sclerosis the immune system functions both to clear virus infection but also to exacerbate the pathogenic response which mediates myelin and axonal injury. The hypothesis to be tested is that antigens encoded by the TMEV genome are critical for protective immunity (resistance) but possibility may also contribute to immunopathology (susceptibility). The experiments will utilize a series of transgenic mice expressing independent three continuous regions of the TMEV genome. Transgenic mice have been created under control of a class I continuous regions of the TMEV genome. Transgenic mice have been created under control of a class I promoter expressing region I coding sequence 5' of VP1 (L, VP4, VP2, and VP3), region II (VP1 coding block), and region III coding sequence 3' of VP1 92A, 2B, 2C, 3A, 3B, 3C, and 3D). By challenging mice expressing TMEV transgenes with infectious virus, we will be able to address the role of immune response to TMEV coding regions in vivo. These experiments will also evaluate demyelination and neurologic deficits in transgenic mice expressing human class II MHC genes infected with TMEV. Finally we will study the phenotype and specificity of the immune response contributing to neurologic deficits utilizing adoptive transfer experiments with perforin deficient mice when injected with TMEV show demyelination but fail to show neurologic deficits. The experiments are expected to provide unique insights into the mechanisms of myelin injury and neurologic deficits with relevance to human multiple sclerosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
1P01NS038468-01A2
Application #
6359223
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
2000-09-01
Project End
2005-08-31
Budget Start
Budget End
Support Year
1
Fiscal Year
2000
Total Cost
$195,164
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
City
Rochester
State
MN
Country
United States
Zip Code
55905
Watzlawik, Jens O; Painter, Meghan M; Wootla, Bharath et al. (2015) A human anti-polysialic acid antibody as a potential treatment to improve function in multiple sclerosis patients. J Nat Sci 1:
Pavelko, Kevin D; Mendez-Fernandez, Yanice; Bell, Michael P et al. (2012) Nonequivalence of classical MHC class I loci in ability to direct effective antiviral immunity. PLoS Pathog 8:e1002541
Mangalam, Ashutosh K; Luckey, David; Giri, Shailendra et al. (2012) Two discreet subsets of CD8 T cells modulate PLP(91-110) induced experimental autoimmune encephalomyelitis in HLA-DR3 transgenic mice. J Autoimmun 38:344-53
Kerkvliet, Jason; Edukulla, Ramakrishna; Rodriguez, Moses (2010) Novel roles of the picornaviral 3D polymerase in viral pathogenesis. Adv Virol 2010:368068
Warrington, Arthur E; Rodriguez, Moses (2010) Method of identifying natural antibodies for remyelination. J Clin Immunol 30 Suppl 1:S50-5
Deb, Chandra; Lafrance-Corey, Reghann G; Zoecklein, Laurie et al. (2009) Demyelinated axons and motor function are protected by genetic deletion of perforin in a mouse model of multiple sclerosis. J Neuropathol Exp Neurol 68:1037-48
Rodriguez, Moses; Warrington, Arthur E; Pease, Larry R (2009) Invited Article: Human natural autoantibodies in the treatment of neurologic disease. Neurology 72:1269-76
Rodriguez, Moses; Zoecklein, Laurie; Papke, Louisa et al. (2009) Tumor necrosis factor alpha is reparative via TNFR2 [corrected] in the hippocampus and via TNFR1 [corrected] in the striatum after virus-induced encephalitis. Brain Pathol 19:12-26
Wright, Brent R; Warrington, Arthur E; Edberg, Dale D et al. (2009) Cellular mechanisms of central nervous system repair by natural autoreactive monoclonal antibodies. Arch Neurol 66:1456-9
Rodriguez, Moses; Zoecklein, Laurie; Kerkvliet, Jason G et al. (2008) Human HLA-DR transgenes protect mice from fatal virus-induced encephalomyelitis and chronic demyelination. J Virol 82:3369-80

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