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 H2 q
haplotype, 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.
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 H2 q
haplotype, 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.
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