PROJECT 2 TITLE: Immune Recognition in a Picornavirus Model of Multiple Sclerosis The proposed studies examine the basis of the limited immune response against a persisting virus in the central nervous system (CNS). Mice infected intracranially with the DA-strain of Theiler's murine encephalitis virus (TMEV) clear the virus using T cell mediated immunity directed by the H-2D class I antigen-presenting molecules that are capable of recognizing the virus and eliminating the injection, yet fail to do so. By using transgenic mice, expressing chimeric class I genes generated by exchanging sequences between the K and D genes, the contribution of regulatory and coding features of the class I genes will be examined to assess the structural basis of the differential use of the class I molecules in the response against TMEV infection. Class I knockout mice will be used to investigate the functional importance of single native K or D antigen- presenting molecules in the development of neurological deficits in the TMEV model of multiple sclerosis. Chimeric transgenes will be intercrossed with the class I knockout MHC haplotype to investigate how differential regulation of single class I antigen presenting molecules will influence the pathology of disease. Recently, developments in our knowledge about the specificity of the anti-TMEV immune response, will permit us to specifically delete the immune response to the immunodominant viral peptide recognized by CD8+ T cells in H-2b mice. This approach will enable us to investigate the importance of the peptide dominant response in host resistance to persistent virus injection and the development of neurological deficits in persistently infected animals.
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