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Title: Cellular interactions between lymphocytes and retinal endothelial cells
Author: Wang, Yufei
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 1994
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Cellular interactions between lymphocytes and endothelial cells derived from retinal and brain microvasculatures are believed to play an important part in the pathogenesis of inflammatory diseases of the central nervous system. In this in vitro study we have investigated these interactions in two aspects; (1) lymphocyte adhesion to and migration across retinal endothelial cells, and (2) antigen presenting properties of retinal and brain endothelial cells. Under normal conditions the level of lymphocyte adhesion to retinal endothelial cells was around 5 %, but this low level of adhesion could be significantly upregulated following endothelial treatment with the cytokines, IFN-γ, IL-1 and IL-4, astrocyte conditioned medium and forskolin. Lymphocyte activation with Con A also increased the adhesion which could be further augmented by activating the endothelial cells with the cytokines, astrocyte conditioned medium and forskolin. Although CD8+ T cells in normal and Con A activated lymphocyte populations adhered to endothelial cells more efficiently than CD4+ T cells, the antigen-specific activated CD4+ T-cell lines (S-Ag specific T cell lines) exhibited the greatest degree of adhesion and were also capable of migrating across retinal endothelial monolayers. The role of adhesion molecules in lymphocyte adhesion and migration has been examined. Lymphocytes express both LFA-1 and VLA-4 and activation of lymphocytes with Con A and S-Ag can increase the expression of LFA-1, but not VLA-4. Resting cultured retinal endothelial cells express ICAM-1 and its expression was significantly increased by IFN-γ and IL-1. Treatment of lymphocytes with the monoclonal antibodies to LFA-1 and VLA-4 significantly inhibited the adhesion of Con A activated lymphocytes and S-Ag specific T cell lines to both resting and IL-1 activated retinal endothelial cells. Pre-incubation of retinal endothelial cells with the monoclonal antibody to ICAM-1 only showed an inhibitive effect on the adhesion of S-Ag specific T cell lines, but not Con A activated lymphocytes. Furthermore, the antibodies to LFA-1 and ICAM-1 also blocked the migration of S-Ag specific T cell lines across both resting and IL-1 activated endothelial monolayers and the antibody to VLA-4 only inhibited the migration across IL-1 activated endothelial monolayers. Cultured retinal and brain endothelial cells are capable of expressing MHC class II molecules following treatment of IFN-γ. With both sets of endothelial cells, only class II I-A, but not I-E molecules, could be induced significantly by day 3 with brain EC expressing lower levels of I-A. IFN-γ also caused a concomitant increase in the level of MHC class I molecules. In comparison with expression of adhesion molecules, induced expression of MHC class II molecules appeared to be slower than enhanced expression of ICAM-1 which occurred within 18 hours following treatment with IFN-γ. Retinal and brain EC were capable of presenting S-antigen to S-antigen specific CD4+ T-cell lines resulting in both T-cell proliferation and cytotoxicity. In contrast to the cytotoxic effect which was demonstrated with confluent endothelial monolayers, significant T-cell proliferation was only seen when subconfluent, rather than confluent endothelial cells were used as the antigen presenting cells. Optimal T-cell proliferation was observed at the ratio of T cells to the endothelial cells in 2:5. Subconfluent endothelial cells also resulted in a greater IL-2 production than confluent cells. Although retinal endothelial cells were capable of producing TGF-B, removal of this factor with the anti-TGF-B monoclonal antibody from the subconfluent proliferation assay attenuated the T-cell response. Contrary to these findings, the addition of exogenous TGF-B to the media in the antigen presentation assays with either confluent or subconfluent endothelial cells did not affect the degree of T-cell proliferation and IL-2 production. Despite demonstrating significant T cell responses to retinal and brain endothelial cell antigen presentation, they remained less efficient than professional antigen presenting cells such as thymocytes.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available