Inhibition of experimental allergic encephalomyelitis in the Lewis rat by paclitaxel.
Experimental allergic encephalomyelitis (EAE), an animal model for multiple sclerosis (MS), is useful for preclinical testing for agents to be considered for treatment for this human demyelinating disease. Microtubules in lymphocytes play an important role in the cascade of human T cell activation, and paclitaxel (PTX), a microtubule stabilizer, can inhibit T cell function. A new formulation of micellar PTX, free of Cremophor and ethanol, was tested for its effect on the induction of EAE in Lewis rats. Adoptive EAE was induced with an encephalitogenic T cell line activated with guinea pig myelin basic protein (GP MBP) peptide 68-88. PTX (10 mg/kg) was administered 24 and 72 h after cell transfer. The clinical signs, fulminating in controls, were completely blocked by PTX, but mild CNS inflammation remained unaltered. A similar dose of PTX, given on days 6 and 8 to animals developing active EAE after immunization with GP MBP peptide 68-88 in complete Freund's adjuvant, greatly reduced the severity of paralysis and delayed the onset of disease by 8-9 days. Marked weight loss and severe toxicity were noted with higher and more prolonged administration. In vitro micellar PTX inhibited activation of encephalitogenic T cells by both specific antigen and mitogen. Lower doses and longer treatment programs may provide effective treatment with acceptable adverse effects with this agent in the treatment of inflammatory demyelinating disease.
Cao
L
L
Department of Neurology, University of Alabama at Birmingham, 619 19th Street South, JT 1205, Birmingham, AL 35249-7340 , USA.
Sun
D
D
Cruz
T
T
Moscarello
M A
MA
Ludwin
S K
SK
Whitaker
J N
JN
D000595:Amino Acid Sequence; D000818:Animals; D000941:Antigens / Q000276:immunology; D002626:Chemistry, Pharmaceutical; D004305:Dose-Response Relationship, Drug; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D005260:Female; D005620:Freund's Adjuvant; D006168:Guinea Pigs; D007116:Immunization, Passive; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects; D008823:Micelles; D008969:Molecular Sequence Data; D009103:Multiple Sclerosis / Q000188:drug therapy*; D004676:Myelin Basic Protein / Q000276:immunology; D017239:Paclitaxel / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D010243:Paralysis / Q000188:drug therapy / Q000517:prevention & control; D010446:Peptide Fragments / Q000276:immunology; D051381:Rats; D011917:Rats, Inbred Lew; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D015431:Weight Loss / Q000187:drug effects
D000941:Antigens; D008823:Micelles; D004676:Myelin Basic Protein; D010446:Peptide Fragments; C079716:myelin basic protein 68-88; D005620:Freund's Adjuvant; D017239:Paclitaxel