Short-term treatment with interferon-alpha/beta promotes remyelination, whereas long-term treatment aggravates demyelination in a murine model of multiple sclerosis

The mechanisms by which type I interferons (IFN) reduce the rate and severi ty of exacerbations in multiple sclerosis are unknown. We utilized a model of multiple sclerosis to determine the extent of demyelination and remyelin ation in Theiler's murine encephalomyelitis virus (TMEV)-infected SJL/J mic e treated with mouse IFN-alpha/beta for a short (5 weeks) or a long (16 wee ks) period. AII mice were chronically infected with TMEV to simulate the cl inical situation in multiple sclerosis. Short-term IFN-alpha/beta treatment increased the percent of remyelinated spinal cord white matter by threefol d when compared with phosphate-buffered saline (PBS) treatment (P < 0.02), but it did not affect the extent of demyelination. In contrast, long-term I FN-alpha/beta treatment increased the extent of demyelination by twofold (P < 0.03). Long-term treatment increased the absolute area of remyelination, but the percent remyelination as a function of area of demyelination was n ot changed because of increased demyelination, An immunomodulatory mechanis m may have contributed to the effect of IFN-alpha/beta on white matter path ology because treated mice had higher anti-TMEV IgGs in serum and demonstra ted decreased numbers of B and T lymphocytes infiltrating the central nervo us system (CNS). There was no correlation between the level of anti- IFN-al pha/beta antibodies and the extent of demyelination or remyelination. These results indicate that the length of type I IFN treatment may have paradoxi cal effects on demyelination and remyelination. J. Neurosci. Res. 59. 661-6 70, 2000. (C) 2000 Wiley-Liss, Inc.