TNF-ALPHA TRANSGENIC AND KNOCKOUT MODELS OF CNS INFLAMMATION AND DEGENERATION

Tumour necrosis factor-alpha (TNF-alpha) plays a central role in infla mmatory events including those taking place in the central nervous sys tem (CNS), and has been implicated as a key pathogenicc mediator in se veral human inflammatory, infectious and autoimmune CNS disorders. Usi ng transgenic and gene knockout mice we have investigated the role of deregulated TNF-alpha production in the CNS. We show that the overexpr ession of wild-type murine or human TNF-alpha transgenes by resident C NS astrocytes or neurons in sufficient to trigger a neurological disor der characterised by ataxia, seizures and paresis, with histopathologi cal features of chronic CNS inflammation and white matter degeneration . Furthermore, we show that transmembrane human TNF-alpha is sufficien t to trigger CNS inflammation and degeneration when overexpressed by a strocytes but not by neurons, indicating that target cells mediating t he neuroinflammatory activities of TNF-alpha localise in the vicinity of astrocytes rather than neurons. Our results establish that both sol uble and transmembrane molecular forms of TNF-alpha can play critical roles in vivo in the pathogenesis of CNS inflammation and demyelinatio n, and validate TNF-alpha transgenic and mutant mice as important mode ls for the further study of related human CNS diseases.