LOVASTATIN ATTENUATES EXPERIMENTAL AUTOIMMUNE UVEORETINITIS IN THE B10.RIII MOUSE

Abstract

Abstract: : Purpose:To investigate the effect of the HMG–CoA reductase inhibitor lovastatin on lymphocyte migration across retinal vascular endothelial cells in vitro and the development of experimental autoimmune uveoretinitis (EAU). Methods:Rat retinal endothelial cell (EC) monolayers were pre–treated with lovastatin (0.1–100 µM) for 24h prior to evaluating lymphocyte adhesion and transmonolayer migration. An acute mouse model of EAU was induced in B10.RIII mice by inoculating with 25 µg of human interphotoreceptor retinoid binding protein ^161–180 peptide emulsified in incomplete Freund’s adjuvant supplemented with 60 µg/ml mycobacterium. Animals were then treated with vehicle or lovastatin (20mg/kg/day) from day 5 post inoculation (PI) plus or minus supplemental mevalonolactone (4mg/kg/day) or squalene (2mg/kg/day). Retinal vascular leakage was assessed by fluorescein angiography at day 10 PI and the experiment terminated at the height of disease on day 12. Eyes were prepared for histological examination. Results:Treatment of retinal EC in vitro with lovastatin resulted in a dose dependent inhibition of antigen–specific T–cell transendothelial migration. This effect was reversed by supplementation with mevalonolactone, the downstream product of HMG–CoA reductase, but not by squalene. This is consistent with the inhibition of isoprenoid pyrophosphate synthesis, precursors required for the prenylation and posttranslational activation of Rho GTPase; a key molecule in the endothelial ICAM–1 mediated pathway that facilitates lymphocyte migration. In an acute mouse model of EAU, lovastatin treatment significantly reduced retinal vascular leakage, attenuated the development of clinical disease and inhibited leucocyte migration into the retina. Co–administration of mevalonolactone, but not squalene, resulted in partial reversal of the inhibitory effect of lovastatin. Conclusions:This study demonstrates that in addition to other known immune modulating properties of statins, one of the major therapeutic targets of lovastatin is the inhibition of lymphocyte migration through the vascular blood–retinal barrier. The use of statins alone, or in combination with other immunomodulators, may prove to be beneficial in the treatment of human posterior uveitis. This work was supported by The Wellcome Trust, the Medical Research Council and the Multiple Sclerosis Society UK.

Keywords: inflammation • uveitis–clinical/animal model