Treatment of relapsing paralysis in experimental encephalomyelitis by targeting Th1 cells through atorvastatin.
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.
Aktas
Orhan
O
Institute of Neuroimmunology, Neuroscience Research Center, NWFZ 2680, Charité, 10098 Berlin, Germany. frauke.zipp@charite.de
Waiczies
Sonia
S
Smorodchenko
Alina
A
Dorr
Jan
J
Seeger
Bibiane
B
Prozorovski
Timour
T
Sallach
Stephanie
S
Endres
Matthias
M
Brocke
Stefan
S
Nitsch
Robert
R
Zipp
Frauke
F
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D000069059:Atorvastatin; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D002453:Cell Cycle / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002460:Cell Line; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology; D005260:Female; D005802:Genes, MHC Class II; D006538:Heptanoic Acids / Q000494:pharmacology* / Q000627:therapeutic use*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008798:Mevalonic Acid / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D018991:Myelin Proteolipid Protein / Q000378:metabolism; D010243:Paralysis / Q000188:drug therapy; D010446:Peptide Fragments / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology* / Q000627:therapeutic use*; D012008:Recurrence; D013116:Spinal Cord / Q000473:pathology; D018417:Th1 Cells / Q000187:drug effects* / Q000276:immunology / Q000502:physiology
D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018991:Myelin Proteolipid Protein; D010446:Peptide Fragments; D011758:Pyrroles; C435023:myelin proteolipid protein (139-151); D000069059:Atorvastatin; D008798:Mevalonic Acid