The Journal of Experimental Medicine
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Published online 10 March 2003 doi:10.1084/jem.20021425
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© Rockefeller University Press, 0022-1007/2003/3/725 $5.00
The Journal of Experimental Medicine, Volume 197, Number 6, 725-733

Treatment of Relapsing Paralysis in Experimental Encephalomyelitis by Targeting Th1 Cells through Atorvastatin

Orhan Aktas1, Sonia Waiczies1, Alina Smorodchenko1, Jan Dörr1, Bibiane Seeger1, Timour Prozorovski1, Stephanie Sallach2, Matthias Endres3, Stefan Brocke4, Robert Nitsch2 and Frauke Zipp1

1 Institute of Neuroimmunology, Neuroscience Research Center
2 Department of Cell and Neurobiology, Institute of Anatomy
3 Department of Neurology, Charité, Humboldt University, 10098 Berlin, Germany
4 Department of Pathology, Hebrew University Hadassah Medical School, Jerusalem 91120, Israel

Address correspondence to Frauke Zipp, Institute of Neuroimmunology, Neuroscience Research Center, NWFZ 2680, Charité, 10098 Berlin, Germany. Phone: 149-30-450-539028; Fax: 149-30-450-539906; E-mail: frauke.zipp{at}charite.de

Statins, known as inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, exhibit numerous functions related to inflammation, such as MHC class II down-regulation, interference with T cell adhesion, and induction of apoptosis. Here we demonstrate that both subcutaneous and oral administration of atorvastatin inhibit the development of actively induced chronic experimental autoimmune encephalomyelitis in SJL/J mice and significantly reduce the inflammatory infiltration into the central nervous system (CNS). When treatment was started after disease onset, atorvastatin reduced the incidence of relapses and protected from the development of further disability. Both the reduced autoreactive T cell response measured by proliferation toward the encephalitogenic peptide PLP139–151 and the cytokine profile indicate a potent blockade of T helper cell type 1 immune response. In in vitro assays atorvastatin not only inhibited antigen-specific responses, but also decreased T cell proliferation mediated by direct TCR engagement independently of MHC class II and LFA-1. Inhibition of proliferation was not due to apoptosis induction, but linked to a negative regulation on cell cycle progression. However, early T cell activation was unaffected, as reflected by unaltered calcium fluxes. Thus, our results provide evidence for a beneficial role of statins in the treatment of autoimmune attack on the CNS.

Key Words: EAE • multiple sclerosis • HMG-CoA reductase • T cell • autoimmunity


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