Inhibition of ras by farnesylthiosalicylate significantly reduces the levels of autoantibodies in two animal models of the antiphospholipid syndrome

Background: Stimulation and proliferation of lymphocytes require activation of Ras. S-farnesylthiosalicylic acid (FTS) is a synthetic substance that detaches Ras from the inner cell membrane and induces its rapid degradation. Antiphospholipid antibodies (aPL) are a heterogeneous group of antibodies detected in patients with antiphospholipid syndrome (APS), which is associated with thrombosis, pregnancy losses, and thrombocytopenia. Objective: To examine the effect of FTS treatment on aPL levels in a genetic autoimmune model (the MRL/1pr mice) and in an induced model of APS. Methods: Female Balb/C mice immunized once with β₂-glycoprotein I (β₂-GPI) in complete Freund's adjuvant (CFA) and female MRL/1pr mice were treated intraperitoneally with either FTS (5 mg/Kg/day) or saline 3-5 times a week. aPL and anti-β₂-GPI antibodies were measured by ELISA. Results: FTS treatment 3 times a week resulted in significant decreases of aPL and anti-β₂-GPI antibodies in both animal models. In contrast, more frequent treatment (5 times a week) had no significant effect on autantibody levels in both animal models. We further compared 2 protocols in the induced APS model, one for alternate day treatment and the other for daily treatment on the first 3 days each week, and found a decrease in autoantibody levels only in the alternate day protocol. Conclusions: Inhibition of Ras activation by FTS is effective in decreasing autoantibody levels in models of APS. The differential modulation of immune function by alternate day compared to daily treatment may provide better understanding of the role of Ras activation in this system.