Review article Statins in the treatment of central nervous system autoimmune disease Martin S. Weber a , Sawsan Youssef b , Shannon E. Dunn b , Thomas Prod'homme a , Oliver Neuhaus c , Olaf Stuve d,e , John Greenwood f , Lawrence Steinman b , Scott S. Zamvil a, ⁎ a Department of Neurology and Program in Immunology, University of California, San Francisco, USA b Department of Neurology and Neurological Sciences and Interdepartmental Program in Immunology, Stanford University, Stanford, CA, USA c Department of Neurology, Heinrich Heine University, Düsseldorf, Germany d Department of Neurology, VA North Texas Heath Care System, Medical Service, Dallas, TX, USA e University of Texas Southwestern Medical Center, Dallas, TX, USA f Department of Cell Biology, Institute of Ophthalmology, University College London, London, UK Received 25 March 2006; received in revised form 26 May 2006; accepted 1 June 2006 Abstract Statins, inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, are widely prescribed for their cholesterol-lowering properties to reduce atherogenesis and cardiovascular morbidity. Over recent years, statins have also been shown to exert pleiotropic immunomodulatory effects that might be of therapeutic benefit in autoimmune disorders. The primary mechanism by which statins alter immune function appears to be mediated through the inhibition of post-translational protein prenylation of small GTP-binding proteins and is largely independent of lipid-lowering. In experimental autoimmune encephalomyelitis (EAE), the mouse model for multiple sclerosis (MS), statins prevent or reverse paralysis and were recently shown to exert synergistic benefit when combined with agents approved for MS therapy. Based primarily upon the beneficial effects in EAE, statins are now being tested in patients in MS clinical trials. © 2006 Elsevier B.V. All rights reserved. Keywords: Statins; EAE; Autoimmune disease; MS; Combination therapy Contents 1. Introduction ............................................................. 0 2. Immunomodulatory mechanism of action ............................................. 0 3. Statins in the treatment of experimental CNS autoimmunity .................................... 0 3.1. Modulation of cellular immune function by statins ..................................... 0 3.1.1. Antigen presenting cell expression of MHC class II ................................ 0 3.1.2. Antigen presenting cell expression of co-stimulatory molecules .......................... 0 3.1.3. T lymphocyte proliferation ............................................. 0 3.1.4. T lymphocyte differentiation ............................................ 0 3.2. Inhibition of leukocyte recruitment into the CNS ...................................... 0 3.2.1. Expression of leukocyte and endothelial adhesion molecules ........................... 0 3.2.2. Leukocyte migration and motility ......................................... 0 3.3. Potential effects on neurons and oligodendrocytes ..................................... 0 Journal of Neuroimmunology xx (2006) xxx – xxx MODEL 5 JNI-474070; No of Pages 9 www.elsevier.com/locate/jneuroim ⁎ Corresponding author. Department of Neurology, University of California, San Francisco, 513 Parnassus Avenue, S-268, San Francisco, CA 94143, USA. Tel.: +1 415 502 7395; fax: +1 415 502 8512. E-mail address: zamvil@ucsf.neuroimmunol.org (S.S. Zamvil). 0165-5728/$ - see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.jneuroim.2006.06.006 ARTICLE IN PRESS