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 conside red for treatment for this human demyelinating disease. Microtubules in lym phocytes 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(R) and ethanol, was tested for its effect on the induction of EAE in Lewis rats. Adoptive EAE w as induced with an encephalitogenic T cell line activated with guinea pig m yelin 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 contro ls, were completely blocked by PTX, but mild CNS inflammation remained unal tered. A similar dose of PTX, given on days 6 and 8 to animals developing a ctive 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 w ith higher and more prolonged administration. In vine micellar PTX inhibite d activation of encephalitogenic T cells by both specific antigen and mitog en. Lower doses and longer treatment programs may provide effective treatme nt with acceptable adverse effects with this agent in the treatment of infl ammatory demyelinating disease. (C) 2000 Elsevier Science B.V. All rights r eserved.