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Inhibition of Theiler's virus-mediated demyelination by peripheral immune tolerance induction
W J Karpus1, J G Pope, J D Peterson
1Department of Microbiology, Northwestern University Medical School, Chicago, IL 60611, USA.
Abstract:
Theiler's murine encephalomyelitis virus (TMEV), a member of the cardiovirus subfamily of the Picornaviridae, is a natural pathogen of mice. Thirty to 60 days following intracerebral infection with TMEV, susceptible inbred mouse strains develop a chronic, progressive, T cell-mediated inflammatory demyelinating disease of the central nervous system (CNS) characterized by spastic hind limb paralysis and a lifelong persistent CNS virus infection. We have examined the effect of peripheral virus-specific tolerance on the development of demyelinating disease. Treatment of SJL/J mice with TMEV-coupled, ethyl carbodiimide-treated splenocytes either before or after infection with live TMEV prevented the development of clinical disease, including inflammation and demyelination in the CNS. Prevention of clinical disease was paralleled by significant reductions in virus-specific immune responses, including delayed type hypersensitivity and T cell proliferative responses. Tolerance induction resulted in a significant reduction in the absolute numbers of mononuclear cells infiltrating the CNS, particularly the CD4+IL-2R+ T cell subset, 3, 5, and 8 wk postinfection. In contrast, tolerance induction had no effect on the numbers of CD8+IL-2R+ T cells infiltrating the CNS. Treatment with TMEV-coupled splenocytes failed to prevent the development of relapsing experimental autoimmune encephalomyelitis, demonstrating the specificity of in vivo tolerance induction. Prevention of demyelinating disease did not correlate with the increased TMEV-specific Ab responses observed in tolerized mice. These results indicate that induction of immune tolerance to TMEV can down-regulate a chronic immunopathogenic disease directed against virus Ag persisting in the CNS that normally results in a progressive demyelinating disease similar to multiple sclerosis.
Insights
Inducing immune tolerance to Theiler's murine encephalomyelitis virus (TMEV) prevents central nervous system demyelinating disease in mice. This approach reduces T cell infiltration and clinical symptoms, offering insights into autoimmune disease management.
Area of Science:
- Neuroimmunology
- Virology
- Immunology
Background:
- Theiler's murine encephalomyelitis virus (TMEV) causes chronic, progressive T cell-mediated demyelinating disease in mice.
- This disease resembles multiple sclerosis, featuring CNS inflammation, paralysis, and persistent infection.
Purpose of the Study:
- To investigate the effect of peripheral virus-specific immune tolerance on TMEV-induced demyelinating disease.
- To determine if inducing tolerance can prevent or mitigate CNS pathology and immune responses.
Main Methods:
- SJL/J mice were treated with TMEV-coupled splenocytes before or after TMEV infection.
- Immune responses, including T cell proliferation, delayed type hypersensitivity, and CNS immune cell infiltration, were assessed.
- Experimental autoimmune encephalomyelitis (EAE) was used to confirm tolerance specificity.
Main Results:
- Tolerance induction prevented clinical disease, CNS inflammation, and demyelination.
- Tolerized mice showed reduced virus-specific immune responses and decreased infiltration of CD4+IL-2R+ T cells in the CNS.
- Tolerance did not affect CD8+IL-2R+ T cells or prevent EAE, indicating specificity.
Conclusions:
- Peripheral immune tolerance effectively down-regulates TMEV-induced chronic immunopathogenic CNS disease.
- This strategy mitigates demyelination by reducing pathogenic T cell responses against persistent viral antigens.
- The findings suggest potential therapeutic approaches for demyelinating diseases like multiple sclerosis.