INHIBITION OF ACUTE, EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS BY THESYNTHETIC IMMUNOMODULATOR LINOMIDE

Linomide (LS-2616, quinoline-3-carboxamide) is a synthetic immunomodul ator that stimulates natural killer cell activity and activates severa l lymphocytic subpopulations in experimental animals and humans. In th is study we determined the effect of oral treatment with linomide on t he development of experimental autoimmune encephalomyelitis, an animal model for immune-mediated human demyelinating disorders. Experimental autoimmune encephalomyelitis was induced in SJL/J mice and in an outb red strain of rats (Sabra) by subcutaneous injection of spinal cord ho mogenate in adjuvant followed by inoculation with Bordetella pertussis . Linomide was administered in drinking water, at an estimated dose of 50 to 100 mg/kg/day. None of the linomide-created mice (0/41) and Sab ra rats (0/15) developed any clinical or pathological signs of experim ental autoimmune encephalomyelitis, whereas almost all control animals (48/53 and 18/19, respectively) were severely paralyzed and 64.5% die d from the disease. Lymphocytes obtained from linomide-treated animals had reduced in vitro proliferative responses to guinea pig myelin bas ic protein, proteolipid protein of the myelin, and tuberculin-purified protein derivative, unlike antigen-independent proliferation which wa s rather unaffected. Natural killer cell activity (tested by a cytotox ic assay on radiolabeled YAC-1 target cells) was significantly enhance d in mice treated with linomide. Our results indicate that modulation of the immune system with linomide leads to complete inhibition of exp erimental autoimmune encephalomyelitis in the absence of systemic immu nosuppression. Linomide could therefore be of use in future clinical t rials for the treatment of human autoimmune demyelinating disorders.