IMMUNOPATHOLOGY OF THE CENTRAL NERVOUS SYSTEM

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The goal of this project is to characterize the components of the central nervous system (CNS) immune response for the purpose of developing specific strategies of immunomodulation. In the forthcoming period we will focus on the immunological alterations of vessels in the animal model experimental allergic encephalomyelitis (EAE) as an archetype of neuroimmunological disease. Endothelial cell expression of Ia, one of the gene products of the major histocompatibility locus, and fibronectin, a plasma glycoprotein which is deposited in inflammatory foci, will be studied in acute and chronic EAE using immunoelectron microscopy to elucidate their in situ roles. Induction of altered endothelial cell Ia and fibronectin expression by activated T cells and their soluble products, lymphokines, will be examined in the skin and CNS to define the cellular and molecular basis of endothelial cell activation. To correlate findings from animal studies with human disease processes, alterations of endothelial cells will be studied in human demyelinating and inflammatory conditions using immunoperoxidase staining of tissue sections. Precise in situ and in vivo characterization of chronic EAE induced by sensitization with myelin proteolipid in guinea pigs and rabbits will be performed using monoclonal antibody staining in tissue sections and in flow cytometry of peripheral blood to determine the role of this myelin component in the immune response to whole CNS tissue. EAE induced by sensitization with whole tissue in guinea pigs will be modulated in vivo by treatment with an anti-T cell and anti-Ia monoclonal antibodies. An understanding of the immunologic parameters, particularly the endothelial cell alterations and immunoregulatory mechanisms, which contribute to the clinical and histological expression of EAE may be applicable to understanding the pathogenesis and designing specific immunotherapy of multiple sclerosis. Knowledge of the effector mechanisms of EAE may have broader implications to understanding autoimmunity and inflammation outside of the CNS.