The immunoregulation of T cell function by CNS endothelium
The presence of inflammatory cells within the central nervous system (CNS) including the retina is characteristic of disease states such as human uveitis and multiple sclerosis, both CD4+ T cell mediated immune inflammatory diseases. Normal CNS is devoid of inflammatory cells and is maintained by the specialized nature of the isolated microenvironments. The blood brain and blood retinal barriers (BBB, BRB) composed of highly specialized endothelial cells physically protect the CNS by regulating immune cell entry. The CNS is actively protected by immune privilege in which the local environment is able to suppress potentially devastating immune reactions, through the local expression of FasL and production of cytokines such as TGF-p. Additionally a role for a group of compounds called Statins has been described in the prevention of leukocyte migration from blood vessels to the sites of atherosclerotic lesions. This study aims to determine potential mechanisms by which microvascular endothelial cells (EC) of the CNS are able to regulate T lymphocyte function, and whether these mechanisms are implicated in disease. The effects of statins on an inflammatory disease of the CNS were also investigated. An in vitro model of the BBB was used to investigate the immunomodulatory effects of EC upon T cells. A transwell insert system was employed to investigate the effects on T cells of co-culture with EC whilst preventing cell-to-cell contact and also, the effect of transmigration through EC monolayers. Studies were also undertaken to investigate potential mechanisms by which this regulation may occur. The effect of statins was investigated using two models of Experimental Autoimmune Uveoretinitis (EAU) as a model of human posterior Uveitis. EAU was induced using SAg peptide or IRBP peptide and the effects of daily administration of statin were assessed using Fluorescein Angiography. Retinal sections were also examined by classical histology. The effects of statins were also investigated using an in vitro model of the BRB, time lapse microscopy and flow cytometry. The effects of statins on T cell function were assessed ex vivo by splenocyte proliferation assays.