FRI0265 The effect of mycophenolate mofetil on disease development in the gld.apoe-/- mouse model of accelerated atherosclerosis and systemic lupus erythematosus

Background Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that is characterized by autoantibody production and inflammatory disease involving multiple organs. Premature atherosclerosis is a common complication of SLE and results in substantial morbidity and mortality from cardiovascular disease (CVD). The reasons for the premature atherosclerosis in SLE are incompletely understood, although chronic inflammation is thought to play an important role. There is currently no known preventative treatment of premature atherosclerosis in SLE. Mycophenolate mofetil (MMF) is an immunosuppressive agent that is commonly used for treatment of patients with SLE. Findings suggest a potential role for MMF in the treatment of atherosclerosis. Objectives To determine if MMF is effective in the treatment of lupus-associated atherosclerosis, including premature atherosclerosis development. Methods We treated gld.apoE-/- mice, a model of SLE and atherosclerosis, with MMF. We maintained seven-week old gld.apoE-/- mice on a high cholesterol Western diet with or without MMF. We studied atherosclerosis and lupus development as previously described. Results After 12 weeks on diet, mice receiving MMF showed decreased atherosclerotic lesion area compared to the control group. A significant decrease in aortic root atherosclerotic lesion area (revealed by staining with Oil red O) was observed in the MMF-treated mice compared to control (p = 0.02). MMF treatment also improved the lupus phenotype, indicated by a significant decrease circulating autoantibody levels (p = 0,001), splenomegaly (p < 0.05) and lymphadenopathy (p = 0.001) size, and ameliorating lupus nephritis (glomerular tuft size, p = 0.002 and cell count, p = 0.004) associated with this model. Conclusions This data suggests that the effects of MMF on the immune system may not only be beneficial for lupus, but also for inflammation driving atherosclerosis. A more extensive analysis of atherosclerosis and SLE in these MMF-treated gld.apoE-/- mice will need to be performed to fully determine how MMF impacts the accelerated atherosclerosis of our lupus mouse model and potentially bring a better understanding of the link between atherogenesis and autoimmune disease. References: Aprahamian T, Rifkin I, Bonegio R, Hugel B, Freyssinet JM, et al. (2004) Impaired clearance of apoptotic cells promotes synergy between atherogenesis and autoimmune disease. J Exp Med 199: 1121-1131. Disclosure of Interest: C. Richez S