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UBC Theses and Dissertations

In vitro modulation of classic II MHC antigen expression by human cerebral endothelium and endothelial cell-lymphocyte interactions by interferons [gamma] and [beta] Huynh, Hanh Kim


In autoimmune demyelinating disorders of the central nervous system (CNS), the blood-brain-barrier (BBB) becomes permeable to plasma proteins and circulating leukocytes. Studies on Multiple Sclerosis (MS) suggest the involvement of T4⁺ lymphocytes and Ia⁺ macrophages in lesion extension and demyelination. Circulating lymphocytes recognize antigen only when it is complexed with Ia molecules on the surface of antigen presenting cells. Recent studies aiming at defining cell populations in the CNS capable of expressing Ia antigen (Ia Ag) indicate Ia Ag expression by EC, astrocytes, microglia and macrophages in MS lesions, while in experimental allergic encephalomyelitis, Ia Ag expression by brain endothelium has been reported by some, but not other investigators. The role of cerebral endothelium in CNS inflammation, therefore, remains ill defined and rather controversial. The objective of this thesis was to investigate the: 1) Induction of Ia Ag on human brain microvessel endothelial cells (HBMEC) treated with interferons (IFN) γ and β, and 2) modulation of T-lymphocyte adhesion and migration across HBMEC monolayers by IFN- γ and β. To address these issues, an in vitro model of the human BBB was utilized. The results indicate that HBMEC do not constitutively express Ia Ag. Treatment with IFN- γ, not β, results in de novo, polarized expression of Ia Ag. Co-incubation with IFN- β downregulates the IFN γ -induced Ia Ag expression. Treatment with IFN- γ, not β, induces morphological and functional changes of HBMEC associated with increased permeability to macromolecules. IFN- γ induced changes do not appear in cultures incubated with both cytokines. Treatment of HBMEC with IFN- γ upregulates the adhesion and migration of resting and activated T lymphocytes across the monolayers. T-lymphocyte activation alone greatly augments both processes. Treatment with IFN- β has no effect on lymphocyte adhesion/migration, however, the IFN-γ-mediated increase in adhesion/migration is suppressed by IFN- β. MAb blocking studies suggest a direct role of Ia molecules in adhesion/migration. These studies indicate a potentially important role of HBMEC in CNS inflammation and increase our understanding of some of the factors involved in the recruitment of lymphocytes into chronic inflammatory sites in the CNS. Therapeutic interventions utilizing mAbs against HLA-DR molecules as well as the use of cytokines, such as IFN- β, that can suppress IFN-γ-mediated responses, may have considerable therapeutic potential.

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