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


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.
Karussis
D
D
Department 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
Abramsky
O
O
Grigoriadis
N
N
Chapman
J
J
Mizrachi-Koll
R
R
Niv
H
H
Kloog
Y
Y
D000818:Animals; D000954:Antigens, Surface / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004334:Drug Administration Schedule; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000276:immunology* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005204:Farnesol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D005260:Female; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000502:physiology; D008214:Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D009185:Myelin Proteins / Q000276:immunology / Q000378:metabolism; D009186:Myelin Sheath / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D010243:Paralysis / Q000188:drug therapy / Q000209:etiology / Q000276:immunology; D012459:Salicylates / Q000494:pharmacology*; D015996:Survival Rate; D016896:Treatment Outcome; D018631:ras Proteins / Q000187:drug effects* / Q000378:metabolism
D000954:Antigens, Surface; D004791:Enzyme Inhibitors; D009185:Myelin Proteins; D012459:Salicylates; C093323:farnesylthiosalicylic acid; D005204:Farnesol; D018631:ras Proteins