Inhibition of Rho GTPases with protein prenyltransferase inhibitors prevents leukocyte recruitment to the central nervous system and attenuates clinical signs of disease in an animal model of multiple sclerosis

Claire E. Walters, Gareth Pryce, Deborah J R Hankey, Said M. Sebti, Andrew Hamilton, David Baker, John Greenwood, Peter Adamson

Research output: Contribution to journalArticle

Abstract

The ICAM-1-mediated brain endothelial cell (EC)-signaling pathway induced by adherent lymphocytes is a central element in facilitating lymphocyte migration through the tight endothelial barrier of the brain. Rho proteins, which must undergo post-translational prenylation to be functionally active, have been shown to be an essential component of this signaling cascade. In this study, we have evaluated the effect of inhibiting protein prenylation in brain ECs on their ability to support T lymphocyte migration. ECs treated in vitro with protein prenylation inhibitors resulted in a significant reduction in transendothelial T lymphocyte migration. To determine the therapeutic potential of this approach, an animal model of multiple sclerosis, experimental autoimmune encephalomyelitis, was induced in Biozzi ABH mice. Animals treated before disease onset with protein prenylation inhibitors exhibited a dramatic and significant reduction in both leukocyte infiltration into the CNS and clinical presentation of disease compared with untreated animals. These studies demonstrate, for the first time, the potential for pharmacologically targeting CNS EC signaling responses, and particularly endothelial Rho proteins, as a means of attenuating leukocyte recruitment to the CNS.

Original languageEnglish (US)
Pages (from-to)4087-4094
Number of pages8
JournalJournal of Immunology
Volume168
Issue number8
StatePublished - Apr 15 2002

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Dimethylallyltranstransferase
Protein Prenylation
Animal Disease Models
rho GTP-Binding Proteins
Multiple Sclerosis
Leukocytes
Central Nervous System
Biozzi Mice
Brain
Endothelial Cells
Lymphocytes
Prenylation
T-Lymphocytes
Proteins
Autoimmune Experimental Encephalomyelitis
Intercellular Adhesion Molecule-1
Animal Models
Therapeutics

ASJC Scopus subject areas

  • Immunology

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Inhibition of Rho GTPases with protein prenyltransferase inhibitors prevents leukocyte recruitment to the central nervous system and attenuates clinical signs of disease in an animal model of multiple sclerosis. / Walters, Claire E.; Pryce, Gareth; Hankey, Deborah J R; Sebti, Said M.; Hamilton, Andrew; Baker, David; Greenwood, John; Adamson, Peter.

In: Journal of Immunology, Vol. 168, No. 8, 15.04.2002, p. 4087-4094.

Research output: Contribution to journalArticle

Walters, Claire E. ; Pryce, Gareth ; Hankey, Deborah J R ; Sebti, Said M. ; Hamilton, Andrew ; Baker, David ; Greenwood, John ; Adamson, Peter. / Inhibition of Rho GTPases with protein prenyltransferase inhibitors prevents leukocyte recruitment to the central nervous system and attenuates clinical signs of disease in an animal model of multiple sclerosis. In: Journal of Immunology. 2002 ; Vol. 168, No. 8. pp. 4087-4094.
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