CHARACTERIZATION OF THE CELLULAR AND CYTOKINE RESPONSE IN THE CENTRAL-NERVOUS-SYSTEM FOLLOWING SEMLIKI-FOREST-VIRUS INFECTION

Cytokines are important mediators in the pathogenesis of central nervo us system (CNS) inflammatory diseases including multiple sclerosis (MS ), experimental allergic encephalomyelitis (EAE), viral encephalitis a nd virus induced demyelinating diseases. We have used immunohistochemi cal techniques to characterize the mononuclear cell infiltrate and cyt okine profiles in the CNS following infection of mice with the demyeli nating A7(74) strain of Semliki Forest virus (SEV), an important viral model of MS. Mononuclear cell infiltrates in the CNS, first observed at 3 days and maximal during clearance of infectious virus, were compr ised predominantly of CD8(+) lymphocytes. F4/80(+) macrophage/microgli a and CD45/B220(+) B lymphocytes were most numerous during the subsequ ent phase of demyelination. CD4(+) T-lymphocytes were observed at low levels throughout infection. By immunostaining MHC class I, IL-1 beta; IL-3 and TGF beta 1 were constitutively expressed in normal mice and were upregulated following infection. MHC class II, IL-1 alpha, IL-2, IL-2R, TNF-alpha and IL-6 were strongly upregulated in the CNS of SFV- infected mice and mice with chronic relapsing EAE. The spatial and tem poral distribution of these cytokines during the course of disease was analysed. Whereas IL-1 alpha, IL-1 beta, IL-10, and TGF beta 1 were o bserved on day 3 following infection GMCSF, IL-2 and TNF alpha were fi rst apparent at day 7 when the cellular infiltration in the CNS was mo st intense. In contrast IFN gamma and IL-6 were first observed on day 10 prior to the demyelination phase of disease. Cytokines in the lesio ns of demyelination suggest a role in the pathogeneisis of myelin dama ge. Based on cytokine profiles no clear bias of either a Th1 or Th2 re sponse was observed in the CNS during infection.