Interferon-gamma in progression to chronic demyelination and neurological deficit following acute EAE

The cytokine interferon-gamma (IFN gamma) is implicated in the induction of acute CNS inflammation, but it is less clear what role if any IFN gamma pl ays in progression to chronic demyelination and neurological deficit. To ad dress this issue, we have expressed IFN gamma in myelinating oligodendrocyt es of transgenic mice. MHC I immunostaining and iNOS mRNA were upregulated in their CNS, but such transgenic mice showed no spontaneous CNS inflammati on or demyelination, and the incidence, severity, and histopathology of exp erimental autoimmune encephalomyelitis (EAE) were similar to nontransgenic controls. In contrast to control mice, which remit from EAE with resolution of glial reactivity and leukocytic infiltration, transgenics showed chroni c neurological deficits. While activated microglia/macrophages persisted in demyelinating lesions for over 100 days, CD4(+) T lymphocytes were no long er present in CNS. IFN gamma therefore may play a role in chronic demyelina tion and long-term disability following the induction of demyelinating dise ase. Because IFN gamma may have neural as well as immune-infiltrating origi ns, these findings generate a new perspective on its role in the CNS.