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dc.contributor.authorWeiss, Jonathan Mark
dc.identifier.citationSource: Dissertation Abstracts International, Volume: 61-02, Section: B, page: 7220.;Advisors: Joan W. Berman.
dc.description.abstractThe blood-brain barrier (BBB) serves as a physical and immunological barrier that protects the central nervous system (CNS). It is formed, in part, by interactions between endothelial cells (EC) and astrocytes. During the pathogenesis of CNS inflammatory diseases, such as multiple sclerosis and FHV-1 encephalitis, the BBB may become leaky and permit, or even facilitate, the passage of leukocytes into the CNS. We previously characterized a tissue culture model of the human BBB in which umbilical vein EC are cocultured with astrocytes on opposite sides of a porous insert. EC, when in direct contact with astrocytes, expressed the BBB markers, glucose transport-1 and gamma-glutamyl transpeptidase. We now characterized the contributions of cytokines, chemokines and adhesion molecules to leukocyte transmigration across cocultures. Exogenous monocyte chemoattractant protein (MCP)-1 induced the dose-dependent transmigration of monocytes. We treated cocultures with cytokines that may! be present in the CNS during inflammation. Supernatants of cytokine-treated cocultures had significant MCP-1 protein, but not other chemokines, such as MIP-1alpha, MIP-1beta and RANTES. Astrocytes were the source of 85% of the MCP-1 detected in cocultures. Cytokine treatments induced monocyte transmigration that was dependent upon MCP-1. Activated lymphocytes also transmigrated and this was partially inhibited by blocking MCP-1. The adhesion molecules, ICAM-1 and E-selectin, but not VCAM-1, played significant roles in mediating monocyte transmigration. Similar findings were observed using cocultures of brain microvascular EC with astrocytes. The HIV-1 transactivator protein, Tat, also contributed to the transmigration process. HIV-1 Tat induced monocyte transmigration that was dependent upon astrocyte-derived MCP-1 expression. Tat enhanced ICAM-1 and E-selectin expression on EC alone or in cocultures. Furthermore, Tat treatment of monocytes increased their expression of the chemokine receptor, CCR5. We characterized the modulation of EC and astrocyte-derived MCP-1 expression by cytokines, including TGF-beta. In EC, TGF-beta downregulated TNFalpha- or IL-1beta-induced MCP-1 expression. In astrocytes, however, TGF-beta induced MCP-1 by itself, further upregulated, MCP-1 expression in combination with either TNalpha or IFNgamma, yet decreased IL-1beta-induced MCP-1 expression. Our findings describe an important role for astrocyte-derived MCP-1 in leukocyte transmigration across the BBB and the regulation of this chemokine by cytokines that may be present during inflammation.
dc.publisherProQuest Dissertations & Theses
dc.titleMechanisms of leukocyte transmigration across the human blood -brain barrier

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