The major goal of this program project is to investigate the immunogenetic basis of demyelination and neurological deficits. The experiments will utilize two excellent models of human multiple sclerosis, i.e. Theiler's virus infection and experimental autoimmune encephalomyelitis. The program project is under the direction of Dr. Moses Rodriguez Professor of Neurology and Immunology of the Mayo Medical School who has ha a long interest in the pathogenesis of demyelination and remyelination in human multiple sclerosis. Members of the Program Project (Drs. Chella S. David, Dr. Larry R. Pease, and Dr. Moses Rodriguez) are well established investigators and Professors of Immunology in the Mayo Medical School. This group has an impressive record of investigations on the immunogenetics in murine models of human disease. Project 1: (Dr. Rodriguez, Principal Investigator) will investigate transgenic expression of Theiler's virus genomes in mice. The experiments will also investigate the mechanisms of decreased demyelinating disease observed in human HLA transgenic mice and address the specificity of the pathogenic immune response important in development of functional neurological deficits following demyelination. Project 2: (Dr. Pease, Principal Investigator) will investigate the basis for H-2K vs. H-2D polarity of anti-TMEV lymphocyte responses in the central nervous system. Experiments will identify the importance of virus-specific CD8+ T cells in the resistance to persistence virus infection and in neuropathology. Project 3: (Dr. David, Principal Investigator) will investigate experimental autoimmune encephalomyelitis in HLA expressing HLA-DR or DQ haplotypes. Experiments will examine the presentation of putative autoantigens linked to MS by HLA-DR and DQ molecules. This Program Project focusing on the immunogenetic basis of demyelination by a group of highly interactive investigators is expected to provide new insights into the pathogenesis of myelin and neural injury in multiple sclerosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS038468-02
Application #
6394086
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Utz, Ursula
Project Start
2000-09-01
Project End
2005-08-31
Budget Start
2001-09-01
Budget End
2002-08-31
Support Year
2
Fiscal Year
2001
Total Cost
$985,119
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

Showing the most recent 10 out of 48 publications