The Role of Class I Haplotype in the Development of Immune Mediated Brain Atrophy in a Murine MS Model (P1.169)

OBJECTIVE: To determine the effects of class I haplotype on brain atrophy development in the TMEV model of MS using transgenic mice. BACKGROUND: Brain atrophy is detectable from the earliest stages of MS, becoming especially prominent in progressive disease. In TMEV infected SJL/J mice we previously demonstrated brain atrophy and its strong association with disability. Similarly to SJL.J mice, FVB/NJ mice are susceptible to demyelination following TMEV infection, but they spontaneously remyelinate and don’t develop disability. We compared FVB/NJ mice with transgenic FVB mice of H2D(b) haplotype, where chronic demyelination is not expected due to efficient viral clearance. DESIGN/METHODS: 14 TMEV infected FVB/D(b) and 7 FVB/NJ mice were followed with monthly 125 micron isometric 7 Tesla MRI for 4 months. Brain atrophy was determined using established methods. Disability was assessed using monthly rotarod assay. Viral load was determined using RT-PCR. Statistical analysis was performed in SigmaPlot using t-tests. RESULTS: Mice with H2D(q) haplotype did not develop brain atrophy (p=0.48) despite chronic demyelination; whereas significant and persistent atrophy was demonstrated within a month in H2D(b) mice (p=0.00047). Rotarod detectable disability did not develop in either strain. Viral load persisted in FVB/NJ but not inH2D(q) mice. CONCLUSIONS: H2D(b) mice clear the virus mainly by CD8 T-cell mediated cytotoxicity directed at neurons, resulting in neuronal loss, leading to brain atrophy development. Altered neuronal maturation in the context of different class I haplotypes may also contribute to this process. Despite significant atrophy, disability doesnt develop in this strain. Although FVB/NJ mice do develop chronic demyelination, we neither observed significant atrophy nor rotarod detectable disability, consistent with the strain9s known characteristic of spontaneous remyelination. In the TMEV model, the development of atrophy is linked with neuronal loss in the brain, dependent on class I haplotype, which determines the efficiency of viral clearance. Brain atrophy only correlates with disability when persistent chronic demyelination also develops. Study Supported by: NIH NINDS and Mayo Clinic Intramural Funds Disclosure: Dr. Pirko has received personal compensation in an editorial capacity for Nanomedicine: Nanotechnology, Biology and Medicine. Dr. Pirko has received research support from Novartis Pharmaceuticals. Dr. Gamez has nothing to disclose. Dr. Atanga has nothing to disclose. Dr. LaFrance has nothing to disclose. Dr. Johnson has nothing to disclose.