The Ras-pathway inhibitor, S-trans-trans-farnesylthiosalicylic acid, suppresses experimental allergic encephalomyelitis

Aim: To evaluate the effects of the synthetic Ras-pathway inhibitor, S-tran s-trans-famesylthiosalicylic acid (FTS) on acute and chronic experimental a utoimmune encephalomyelitis (EAE and CR-EAE). Background: Treatment of EAE, and MS is based on immunosuppression aiming at downregulation. of the prol iferating myelin-reactive lymphocytes. One of the pathways of lymphocyte ac tivation involves the GTP-binding protein Ras. FTS destabilizes the attachm ent of Ras to the cell membrane, resulting in an inhibition of the Ras-medi ated signal transduction pathways. Materials and methods: EAE was induced i n SJL/J mice by immunization with spinal cord homogenate (MSCH) in adjuvant and two i.v. boosts of pertussis antigen and CR-EAE with passive transfer of proteolipid protein (PLP)-activated lymphocytes. Animals were treated da ily starting either from the day of EAE-induction (or cell transfer) or at a later stage, with i.p. injections of FTS (5 mg/kg/day). The clinical seve rity of the disease was evaluated daily and scored using a 0-6 scale. Resul ts: In six separate experiments, 27 of the 38 (71.7%) vehicle-treated anima ls developed clinical signs of EAE compared to 17/38 (44.7%) of the FTS-tre ated mice (p = 0.02, t-test). The maximal average score in the control grou p was 2.94 +/- 2.2, whereas in the FTS group it was significantly lower (1. 63 +/- 2.2, p = 0.01). Mortality was 26.3% and 10.5% in the two groups, res pectively (p = 0.03). When treatment was initiated at a later stage, just b efore the onset of the clinical signs, the protective effect was even more pronounced. A significant suppression of clinical signs was also observed i n the CR-EAE model (p = 0.02). Lymphocyte proliferation assays demonstrated a more than twofold decrease in the reactivity to myelin antigens (MBP and PLP) and downregulation of the activated lymphocytes (expressing the CD62L , and IA-k-MHC Class I markers and the Vb17 T-cell receptor) in the FTS-tre ated group; in vitro FTS suppressed the Ras activity of lymphocytes and inh ibited the proliferative ability of the lymphocytes in a dose-dependent man ner. Conclusions: FTS suppresses EAE by downregulation of myelin-reactive a ctivated T-lymphocytes. Since FTS did not induce generalized immunosuppress ive effects, it may offer significant advantages over the broad immunosuppr essive modalities and may be a candidate treatment for autoimmune diseases, such as MS. (C) 2001 Elsevier Science B.V. All rights reserved.