Intracranial inoculation of susceptible SJL mice with Theiler's murine encephalomyelitis virus (TMEV) results in biphasic disease consisting of early
acute disease, followed by late chronic
demyelinating disease, associated with mononuclear infiltrates and demyelinating lesions. In contrast, resistant C57BL/6 (B6) mice develop only early
acute disease. We employed
cytokine-specific RT-PCR to determine the expression of
cytokine transcripts in the CNS of TMEV-infected SJL and B6 mice. During early
acute disease, we have found a strong proinflammatory (Th1)
cytokine response in the CNS of both TMEV-infected SJL and B6 mice, demonstrated by the expression of transcripts for IFN-gamma,
IL-1,
IL-6,
IL-12p40, and
TNF-alpha. At 8 days postinfection (p.i.),
TGF-beta1 and
TNF-alpha transcripts were present at significantly higher levels (P < 0.01) in the CNS of SJL susceptible mice in comparison to those found in the CNS of B6 mice. Immunohistochemical staining revealed that
TGF-beta protein was expressed in leptomeningeal mononuclear inflammatory cell infiltrates in the brain of SJL mice but not in B6 mice, at 8 days p.i.
TGF-beta may be responsible for the failure of SJL mice to develop an effective anti-TMEV CTL response. During late chronic
demyelinating disease, high levels of proinflammatory Th1
cytokines were found in the CNS of SJL mice, but not B6 mice. Significantly higher levels (P < 0.01) of anti-inflammatory
cytokine transcripts (IL-4, IL-5, and IL-10 (Th2
cytokines) and
TGF-beta) were found in the spinal cord of TMEV-infected SJL mice with chronic
demyelinating disease than in the spinal cord of B6 mice during the same time period (39 or 60 days p.i.). These anti-inflammatory
cytokines may contribute to the downregulation of the proinflammatory response in SJL mice. High levels of
IL-2 transcripts and
protein appeared transiently in the spinal cord of TMEV-infected SJL mice before the onset of
demyelinating disease and coincided with an influx of new T cells into the CNS and/or expansion of remaining T cells that have not been eliminated after viral clearance.