This grant proposal for continuation of the Demyelinating Diseases Center at the University of Maryland describes studies to further investigate mechanisms of demyelination and the interaction among the cells of the nervous system and the immune system. The projects are developed to integrate information derived from the cellular and molecular levels with the events occurring in mammalian central (CNS) and peripheral nervous system (RNS) using cells and tissues derived from animals and humans. In the first of 4 projects, segregated CNS cell populations from rats will be used to study the regulation of cytokine production. Specifically, virus-induced signal pathways involved in tumor necrosis factor (TNF) gene transcription and TNF MRNA stabilization will be investigated. In addition, the effects of TNF on oligodendrocytes which produce and maintain myelin, and on astrocytes will be studied. The second project will explore the mechanisms of class II MHC expression and its regulation by human pathogenic viruses using specified human brain cells. The biology of this class II molecules induced on glial cells on T- cell activation will be delineated. This important project will extend theoretical knowledge developed in animal models into the realm of human tissue. In the third project, the production and role of the IFN-gamma-induced early gene product, crg-2, on CNS immunoregulation, will be studied. This project includes an in vivo rat model using CAM measles virus, an agent which induced crg-2 in brains of infected animals. The fourth and final project continues the ground-breaking studies which have defined an antibody response as central in the pathogenesis of the Guillain-Barre syndrome (GBS). The mechanism by which antibodies damage PNS myelin will be defined and the antigen which is the target for this immunologic attack in GBS will be identified. The possibility that cross- reacting antigens shared by infectious agents and the PNS myelin will be studied. In this way, the link between a recent infection and CBS may be clarified.
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