Atorvastatin fails to prevent the development of autoimmune diabetes despite inhibition of pathogenic beta-cell-specific CD8 T-cells.
Statins, the widely used inhibitors of cholesterol biosynthesis, also have immunomodulatory properties. Statins have recently been shown to have beneficial prophylactic and therapeutic effects in actively induced, short-term animal models of the autoimmune diseases multiple sclerosis and rheumatoid arthritis, leading to clinical trials. We therefore investigated whether statins' protective effects could be reproduced in the nonobese diabetic (NOD) mouse, a spontaneous, chronic model of autoimmune diabetes. Mice were treated with 0, 1, 10, or 50 mg x kg(-1) x day(-1) oral atorvastatin from 6 or 12 weeks of age, without effect on the rate or prevalence of diabetes development, islet infiltration, or islet major histocompatibility complex class II expression. However, there was clear evidence of a disease-relevant immunological effect of statins in vivo, since short-term (12-day) treatment significantly reduced the number of proinflammatory (gamma-interferon-producing) CD8 cells recognizing a dominant pathogenic epitope. This effect was absent in mice treated for longer periods, suggesting that atorvastatin loses efficiency in inhibiting autoantigen-specific T-cells over time. This observation may explain the discrepancy between the reported success of statins in acutely induced models and the lack of it in a chronic, spontaneous model of autoimmune disease and has implications for the adoption of such therapy in humans.
Department of Immunobiology, King's College London, School of Medicine, London, UK.
Biliana
B
Lozanoska-Ochser
Francesca
F
Barone
Costantino
C
Pitzalis
Mark
M
Peakman
D000818:Animals; D000069059:Atorvastatin; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005260:Female; D006538:Heptanoic Acids / Q000494:pharmacology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007371:Interferon-gamma / Q000097:blood; D016753:Interleukin-10 / Q000097:blood; D015847:Interleukin-4 / Q000097:blood; D051379:Mice; D016688:Mice, Inbred NOD; D011758:Pyrroles / Q000494:pharmacology*
D006538:Heptanoic Acids; D000949:Histocompatibility Antigens Class II; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma; D000069059:Atorvastatin