LATE-ONSET CHRONIC INFLAMMATORY ENCEPHALOPATHY IN IMMUNE-COMPETENT AND SEVERE COMBINED IMMUNE-DEFICIENT (SCID) MICE WITH ASTROCYTE-TARGETEDEXPRESSION OF TUMOR-NECROSIS-FACTOR

To examine the role of tumor necrosis factor (TNF)-alpha in the pathog enesis of degenerative disorders of the central nervous system (CNS), transgenic mice mere developed in which expression of murine TNF-alpha was targeted to astrocytes using a glial fibrillary acidic protein (G FAP)-TNF-alpha fusion gene. In two independent GFAP-TNF alpha transgen ic lines (termed GT-8 or GT-2) adult (>4 months of age) animals develo ped a progressive ataxia (GT-8) or total paralysis affecting the lower body (GT-2), Symptomatic mice had prominent meningoencephalitis (GT-8 ) or encephalomyelitis (GT-2) in which large numbers of B cells and CD 4(+) and CD8(+) T cells accumulated at predominantly perivascular site s. The majority of these lymphocytes displayed a memory cell phenotype (CD44(high) CD62L(low), CD25(-)) and expressed an early activation ma rker (CD69). Parenchymal lesions contained mostly CD45(+) high, MHC cl ass II+, and Mac-1(+) cells of the macrophage microglial lineage with lower numbers of neutrophils and few CD4(+) and CD8(+) T cells. Cerebr al expression of the cellular adhesion molecules ICAM-1, VCAM-1, and M AdCAM as well as a number of alpha- and beta-chemokines was induced or upregulated and preceded the development of inflammation, suggesting an important signaling sole for these molecules in the CNS leukocyte m igration. Degenerative changes in the CNS of the GFAP-TNF alpha mice p aralleled the development of the inflammatory lesions and included pri mary and secondary demyelination and neurodegeneration, Disease exacer bation with more extensive inflammatory lesions that contained activat ed cells of the macrophage/microglial lineage occurred in GFAP-TNF alp ha mice with severe combined immune deficiency. Thus, persistent astro cyte expression of murine TNF-alpha in the CNS induces a late-onset ch ronic inflammatory encephalopathy in which macrophage/microglial cells but not lymphocytes play a central role in mediating injury.