Walters, Claire Elizabeth; (2002) Identification and development of theraputic approaches in controlling transvascular leukocyte migration and inflammation in the CNS. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Endothelial Rho proteins are essential signalling molecules that mediate endothelial responses to adherent leukocytes through ICAM-1, allowing them to migrate through brain endothelial monolayers. In order to be functionally active, Rho proteins are required to undergo post-translational prenylation. In vitro inhibition of brain endothelial protein isoprenylation with protein prenyl transferase inhibitors, resulted in a significant reduction in the ability of brain endothelial cells to support transendothelial migration of myelin basic protein (MBP)-specific T-lymphocytes. The effect of these inhibitors was specific for the process of migration and did not significantly affect the ability of T-lymphocytes to adhere to endothelial cells. Protein prenyl transferase inhibitors were also effective at inhibiting leukocyte migration into the CNS and attenuating clinical signs of disease in an in vivo model of neuroinflammation. Similar studies using the 3-hydroxy-3-methylglutaryl Coenzyme A reductase inhibitor, lovastatin to limit the availability of isoprenoid groups for protein prenylation showed a significant reduction in both the transendothelial migration of MBP-specific T-lymphocytes and the infiltration of leukocytes into the CNS. These studies demonstrate the potential of pharmacologically targeting CNS endothelial cell signalling responses, and particularly limiting endothelial protein prenylation, as a means of attenuating leukocyte recruitment to the CNS and subsequent neuroinflammatory disease. Studies with VCAM-1 suggest that it may transduce intracellular signals in brain endothelial cells which may be important in the transvascular migration of monocytes.

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