This program project integrates studies on the potential mechanisms governing tissue damage in neuroimmune diseases of the central and peripheral nervous system. Damage to myelin producing cells by immune cells and their products are central to the pathology of human demyelinating diseases such as multiple sclerosis, Guillain Barre syndrome, inflammatory demyelinating neuropathies (CIPD), some paraproteinemic neuropathies, and acute disseminated encephalomyelitis (ADEM). The projects in this proposal are designed to further investigate the mechanisms by which cytokines, antibodies, and leukocytes themselves effect immune cell trafficking and ultimately damage to glial cells. the animal model experimental autoimmune encephalomyelitis (EAE) will be used in Projects 1 and 2 to further define the role of the activated endothelium in induction and recovery of acute EAE in rats, as well as in susceptibility and resistance in mice. These studies will be integrated with those investigating the importance of the T-effector cell environment in EAE resistance. Particular attention will be paid to cytokine-induced activation mechanisms. In Projects 3 and 4 the roles of immune released cytokines and antibodies in glial cell damage will be investigated using primary Schwann cell cultures. The third project will focus on the potential role products (monokines) released by the activated macrophages which effect Schwann cell repair responses. The mechanisms by which antibodies to glycolipids alter glial cells will be defined in Project 4 and crucial experiments performed to identify the role of glycolipids as receptors. Thus, this program project combines the expertise of senior investigators in the field of neuroimmunology- neurobiology, who will integrate efforts to elucidate basic mechanisms governing neuroimmune damage in demyelinating diseases. Projects will also integrate state-of-the-art approaches to these questions including glial cell culture techniques, confocal laser cytometry, and molecular biology. The individual projects are: Project 1 - Acute EAE: The Role of Endothelial Cell Activation. Project 2 - Resistance Mechanisms in murine Adoptive EAE Project 3 - Effects of Monokines on Schwann Cell Repair Project 4 - Antibodies to Glycoconjugates and Schwann Cell Function
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