The mechanisms responsible for the induction of experimental allergic encephalomyelitis (EAE) are being examined utilizing SJL mice. This model autoimmune disease is characterized clinically by severe hind limb paralysis and pathologically by the presence of an inflammatory response in the central nervous system (CNS) and resulting primary demyelination. The histopathological observation of perivascular infiltration of inflammatory cells into the CNS has led to research concerning the mechanism by which these cells from the systemic circulation migrate across the blood-brain barrier which is composed of cerebrovascular endothelial cells (EC) forming tight junctions. ln addition, all mice in this animal model system recover and develop a chronic relapsing-remitting course of disease. The mechanisms responsible for these relapses and remissions are unknown. Current investigations are focused on the expression and modulation of class II MHC (la) molecules on EC as well as CNS-derived astrocytes and macrophages. The capacity of these cells to express la molecules and to function as antigen-presenting cells is being studied for their possible role in this disease model. Human cerebrovascular EC isolated from fresh brain tissue surgically removed for treatment of idiopathic Epilepsy were also tested for their ability to express la antigen upon treatment with interferon-gamma (IFNgamma). All cell types could be induced to express la antigens by treatment with IFNgamma. The level of expression and the kinetics of induction differed for each cell population. All la-positive cells were also able to function as competent antigen-presenting cells. The mechanism of la antigen induction by IFNgamma treatment of above cells is being examined by culturing cells in the presence of various compounds which were found to modulate la expression. Tumor necrosis factor (TNF) augmented the level of la expression on astrocytes and inhibited la expression on EC, indicating differences between these cells regarding the mechanisms of modulation. The addition of adrenergic agonists such as isoproterenol to EC cultures resulted in significant inhibition in IFNgamma-induced la expression. Experiments utilizing a variety of agonists as well as antagonists were performed to characterize this effect. Simultaneous experiments examining the level of cAMP formation in EC showed that isoproterenol augmented the level of cAMP. The correlation between cAMP formation and la expression indicates a potential interaction between the pathways leading to their formation.
