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 severity of exacerbations in multiple sclerosis are unknown. We utilized a model of multiple sclerosis to determine the extent of demyelination and remyelination in Theiler's murine encephalomyelitis virus (TMEV)-infected SJL/J mice treated with mouse IFN-alpha/beta for a short (5 weeks) or a long (16 weeks) period. All mice were chronically infected with TMEV to simulate the clinical situation in multiple sclerosis. Short-term IFN-alpha/beta treatment increased the percent of remyelinated spinal cord white matter by threefold when compared with phosphate-buffered saline (PBS) treatment (P < 0.02), but it did not affect the extent of demyelination. In contrast, long-term IFN-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 not changed because of increased demyelination. An immunomodulatory mechanism may have contributed to the effect of IFN-alpha/beta on white matter pathology because treated mice had higher anti-TMEV IgGs in serum and demonstrated decreased numbers of B and T lymphocytes infiltrating the central nervous system (CNS). There was no correlation between the level of anti- IFN-alpha/beta antibodies and the extent of demyelination or remyelination. These results indicate that the length of type I IFN treatment may have paradoxical effects on demyelination and remyelination.
Njenga
M K
MK
Department of Veterinary PathoBiology, University of Minnesota, St. Paul, MN, USA.
Coenen
M J
MJ
DeCuir
N
N
Yeh
H Y
HY
Rodriguez
M
M
D000818:Animals; D000855:Anorexia / Q000139:chemically induced; D000998:Antiviral Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000473:pathology; D018188:Cardiovirus Infections / Q000473:pathology / Q000821:virology; D000939:Epitopes; D006968:Hypersensitivity, Delayed / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism; D016898:Interferon-alpha / Q000009:adverse effects / Q000627:therapeutic use*; D016899:Interferon-beta / Q000009:adverse effects / Q000627:therapeutic use*; D051379:Mice; D008815:Mice, Inbred Strains; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D009186:Myelin Sheath / Q000187:drug effects* / Q000502:physiology*; D009836:Oligodendroglia / Q000502:physiology; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000821:virology; D013601:T-Lymphocytes / Q000473:pathology; D017945:Theilovirus / Q000276:immunology / Q000302:isolation & purification; D013997:Time Factors
D000998:Antiviral Agents; D000939:Epitopes; D007074:Immunoglobulin G; D016898:Interferon-alpha; D016899:Interferon-beta