Studies indicate that cholesterol-lowering 3-hydroxy 3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (""""""""statins"""""""") have immunomodulatory properties that may be beneficial in treatment of Th1-mediated autoimmune diseases. Oral atorvastatin (Lipitor) could either prevent or reverse ongoing relapsing or chronic EAE. Atorvastatin treatment induced a Th2 bias that was associated with STAT6 phosphorylation, and promoted differentiation of Th2 cells that adoptively transferred protection to untreated mice. EAE protection persisted after atorvastatin was discontinued, suggesting that atorvastatin treatment induced sustained immunomodulation (tolerance). Mevalonic acid, the product of HMG-CoA reductase, prevented both atorvastatin-induced Th2 differentiation by Th0 cells. The mevalonate pathway involves sequences of enzymatic reactions with branches that lead to the production of different isoprenoid compounds including dolichols, ubiquinone and cholesterol, as well as the postranslation modification (isoprenylation) of small GTP binding proteins (e.g. ras) involved in signal transduction. Thus, the mevalonate pathway is crucial for cell cycle progression and differentiation. We hypothesize that isoprenoid metabolites are necessary for Thl differentiation and that statins mediate Th2 differentiation by inhibiting production of specific mevalonate metabolites. We hypothesize that atorvastatin-induced Th2 cells will mediate bystander suppression. We propose to investigate the role of certain atorvastatin-induced regulatory cytokines in EAE protection. These studies will elucidate the mechanisms involved in atorvastatin-induced immunomodulation and role of the mevalonate pathway in T cell differentiation and regulation.
The Specific Aims are: (1) To identify which metabolites in the branched mevalonate pathway influence T cell activation and differentiation and examine how atorvastatin and other selective inhibitors in isoprenoid metabolism influence signaling and gene transcription during T cell differentiation. (2) Gene microarray will be used to identify additional targets in immunodulation that may be altered by atorvastatin. (3) We will examine whether atorvastatin treatment induces bystander suppression, prevents epitope spreading of T cells and, using autoantigen microarray, inhibits spreading of antibodies. These studies have direct and immediate applicability to the use of statins in treatment of autoimmune disease.
|von Büdingen, H-Christian; Palanichamy, Arumugam; Lehmann-Horn, Klaus et al. (2015) Update on the autoimmune pathology of multiple sclerosis: B-cells as disease-drivers and therapeutic targets. Eur Neurol 73:238-46|
|Weber, Martin S; Prod'homme, Thomas; Youssef, Sawsan et al. (2014) Neither T-helper type 2 nor Foxp3+ regulatory T cells are necessary for therapeutic benefit of atorvastatin in treatment of central nervous system autoimmunity. J Neuroinflammation 11:29|
|Schulze-Topphoff, Ulf; Casazza, Simona; Varrin-Doyer, Michel et al. (2013) Tob1 plays a critical role in the activation of encephalitogenic T cells in CNS autoimmunity. J Exp Med 210:1301-9|
|Varrin-Doyer, Michel; Spencer, Collin M; Schulze-Topphoff, Ulf et al. (2012) Aquaporin 4-specific T cells in neuromyelitis optica exhibit a Th17 bias and recognize Clostridium ABC transporter. Ann Neurol 72:53-64|
|Waubant, E; Pelletier, D; Mass, M et al. (2012) Randomized controlled trial of atorvastatin in clinically isolated syndrome: the STAyCIS study. Neurology 78:1171-8|
|Kim, Susan S; Richman, David P; Zamvil, Scott S et al. (2011) Accelerated central nervous system autoimmunity in BAFF-receptor-deficient mice. J Neurol Sci 306:9-15|
|Zamvil, Scott S; Steinman, Lawrence (2011) Combining statins with interferon ? in multiple sclerosis: think twice, it might not be all right. Lancet Neurol 10:672-3|
|Lalive, Patrice H; Neuhaus, Oliver; Benkhoucha, Mahdia et al. (2011) Glatiramer acetate in the treatment of multiple sclerosis: emerging concepts regarding its mechanism of action. CNS Drugs 25:401-14|
|Nelson, Patricia A; Khodadoust, Mojgan; Prodhomme, Thomas et al. (2010) Immunodominant T cell determinants of aquaporin-4, the autoantigen associated with neuromyelitis optica. PLoS One 5:e15050|
|Weber, Martin S; Prod'homme, Thomas; Patarroyo, Juan C et al. (2010) B-cell activation influences T-cell polarization and outcome of anti-CD20 B-cell depletion in central nervous system autoimmunity. Ann Neurol 68:369-83|
Showing the most recent 10 out of 13 publications