Deletion of Virus-specific T-cells Enhances Remyelination in a Model of Multiple Sclerosis.
We used transgenic expression of capsid antigens to Theiler's murine encephalomyelitis virus (TMEV) to study how the immune response to VP1 and VP2 influences spinal cord demyelination, remyelination and axonal loss during the acute and chronic phases of infection. Expression from birth of capsid antigen under the ubiquitin promoter resulted in tolerance to the antigen and absence of an immune response to the respective capsid antigen following virus infection. The transgenic mice were crossed to B10.Q mice normally susceptible to demyelination but which, when compared to FVB mice of the same H2qhaplotype, show poor remyelination. The major finding in this study was that VP1+ and VP2+ animals featured more remyelination at all three chronic time points (90, 180 and 270 dpi) than transgene-negative controls. Interestingly, at 270 dpi, remyelination in VP1+ mice tended to be higher and more complete than that in VP2+ mice. Compared with transgene- negative controls, VP1+ and VP2+ animals showed similar demyelination in but less only late in the disease (270 dpi). The number of mid-thoracic axons at the last time point correlated with the levels of remyelination. The increase in number of axons in VP1+ mice with remyelination was driven by counts in medium- and large-caliber axons. This study supports the hypothesis that expression of viral capsid proteins as self and subsequent genetic deletion of capsid-specific T cells influences the extent of spinal cord remyelination following Theiler's virus-induced demyelination. We propose that VP1- and, to a lesser extent, VP2-specific CD8+T cells limit and/or prevent the naturally occurring process of remyelination. This finding may have relevance to human multiple sclerosis, as targeted removal of CD8+T cells specific for a yet-to-be-discovered causative peptide may enhance remyelination and prevent axonal loss in patients.
Department of Neurology, Mayo Clinic, Rochester, MN 55905.
Aleksandar
A
Denic
Department of Immunology, Mayo Clinic, Rochester, MN 55905.
Bharath
B
Wootla
Laurie
L
Zoecklein
Moses
M
Rodriguez
Axons; Multiple Sclerosis; Remyelination; TMEV; VP1; VP2