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The Ras-pathway inhibitor, S-trans-trans-farnesylthiosalicylic acid, suppresses experimental allergic
D Karussis1, O Abramsky, N Grigoriadis
1Department of Neurology and Laboratory of Neuroimmunology, Agnes-Ginges Center for Human Neurogenetics, Hadassah Medical Center, Hebrew University, IL-91120, Jerusalem, Israel. karus@cc.huji.ac.il
Aim:
To evaluate the effects of the synthetic Ras-pathway inhibitor, S-trans-trans-farnesylthiosalicylic acid (FTS) on acute and chronic experimental autoimmune encephalomyelitis (EAE and CR-EAE).
Background:
Treatment of EAE and MS is based on immunosuppression aiming at downregulation of the proliferating myelin-reactive lymphocytes. One of the pathways of lymphocyte activation involves the GTP-binding protein Ras. FTS destabilizes the attachment of Ras to the cell membrane, resulting in an inhibition of the Ras-mediated signal transduction pathways.
Materials And Methods:
EAE was induced in 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 daily 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 severity of the disease was evaluated daily and scored using a 0-6 scale.
Results:
In six separate experiments, 27 of the 38 (71.7%) vehicle-treated animals developed clinical signs of EAE compared to 17/38 (44.7%) of the FTS-treated mice (p=0.02, t-test). The maximal average score in the control group 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, respectively (p=0.03). When treatment was initiated at a later stage, just before the onset of the clinical signs, the protective effect was even more pronounced. A significant suppression of clinical signs was also observed in 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-treated group; in vitro FTS suppressed the Ras activity of lymphocytes and inhibited the proliferative ability of the lymphocytes in a dose-dependent manner.
Conclusions:
FTS suppresses EAE by downregulation of myelin-reactive activated T-lymphocytes. Since FTS did not induce generalized immunosuppressive effects, it may offer significant advantages over the broad immunosuppressive modalities and may be a candidate treatment for autoimmune diseases, such as MS.
Insights
S-trans-trans-farnesylthiosalicylic acid (FTS) effectively suppressed experimental autoimmune encephalomyelitis (EAE) by reducing myelin-reactive T-lymphocyte activity. This Ras-pathway inhibitor shows promise for treating autoimmune diseases like multiple sclerosis (MS).
Area of Science:
- Neuroimmunology
- Immunopharmacology
- Autoimmune disease research
Background:
- Current treatments for EAE and MS rely on immunosuppression to reduce myelin-reactive lymphocyte proliferation.
- The Ras signaling pathway is crucial for lymphocyte activation.
- FTS inhibits Ras-mediated signal transduction by destabilizing Ras membrane attachment.
Purpose of the Study:
- To investigate the therapeutic effects of FTS, a synthetic Ras-pathway inhibitor, on acute and chronic experimental autoimmune encephalomyelitis (EAE).
Main Methods:
- EAE and chronic EAE (CR-EAE) were induced in mice.
- Animals received daily intraperitoneal injections of FTS (5 mg/kg/day) starting from disease induction or at a later stage.
- Clinical severity was scored daily, and lymphocyte proliferation assays were performed.
Main Results:
- FTS treatment significantly reduced the incidence and severity of EAE compared to vehicle controls (44.7% vs 71.7%).
- FTS treatment also suppressed clinical signs in the CR-EAE model.
- Lymphocyte proliferation assays showed reduced reactivity to myelin antigens and downregulated activated lymphocytes in FTS-treated mice.
Conclusions:
- FTS effectively suppresses EAE by downregulating myelin-reactive T-lymphocytes.
- FTS demonstrates potential as a targeted treatment for autoimmune diseases like MS, offering advantages over generalized immunosuppression.