INCREASED SEVERITY OF EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS, CHRONIC MACROPHAGE MICROGLIAL REACTIVITY, AND DEMYELINATION IN TRANSGENIC MICE PRODUCING TUMOR-NECROSIS-FACTOR-ALPHA IN THE CENTRAL-NERVOUS-SYSTEM/

Tumor necrosis factor-alpha (TNF-alpha) is an inflammatory cytokine im plicated in a number of autoimmune diseases. Apoptotic cell death is i nduced by TNF-alpha in vitro, and has been suggested as one cause of a utoimmune pathology, including autoimmune demyelinating diseases where oligodendrocytes are a target of immune attack. TNF-alpha also regula tes macrophage activity which could contribute to autoimmune inflammat ion. We have expressed TNF-alpha at disease-equivalent levels in the c entral nervous system of transgenic mice, using a myelin basic protein (MBP) promoter. These mice were normal and showed no spontaneous path ology, but they developed experimental autoimmune encephalomyelitis (E AE) with greater severity than nontransgenic controls when immunized w ith MBP in adjuvant. Unlike nontransgenic controls, EAE then progresse d to a nonabating demyelinating disease. Macrophage/microglial reactiv ity was evident in demyelinating lesions in spinal cord, but T cells w ere not detected during chronic disease. The participation of TNF-alph a in the demyelinating process is thus more probably due to the perpet uation of macrophage/microglial activation than to direct cytotoxicity of myelin or oligodendroglia.