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Atorvastatin Fails to Prevent the Development of Autoimmune Diabetes Despite Inhibition of Pathogenic ß-Cell–Specific CD8 T-Cells

¹ Department of Immunobiology, King’s College London, School of Medicine, London, U.K
² Department of Rheumatology, King’s College London, School of Medicine, London, U.K

Address correspondence and reprint requests to Professor Mark Peakman, Department of Immunobiology, King’s College London, School of Medicine, 2nd Floor, New Guy’s House, Guy’s Hospital, London, SE1 9RT, U.K. E-mail: mark.peakman{at}kcl.ac.uk

Abbreviations: CIA, collagen-induced arthritis; CTL, cytotoxic T-lymphocyte; EAE, experimental encephalomyelitis; FITC, fluorescein isothiocyanate; IEC, islet endothelial cell; IFN-, -interferon; IGRP, islet-specific glucose 6-phosphatase catalytic subunit–related protein; IL, interleukin; MHC, major histocompatibility complex; Th1, T-helper 1

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 · kg^–1 · 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 (-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.

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