IMMUNOMODULATION OF AUTOIMMUNITY BY LINOMIDE - INHIBITION OF ANTIGEN PRESENTATION THROUGH DOWN-REGULATION OF MACROPHAGE ACTIVITY IN THE MODEL OF EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS

Linomide (quinoline-3-carboxamide, LS-2616), a synthetic immunomodulat or, protects animals against a variety of experimental autoimmune dise ases. In experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis (MS), linomide blocks both the clinical and histol ogical signs of the disease, without inducing generalized immunosuppre ssion. In the first clinical trial in patients with MS, linomide was s hown to inhibit the progression of the disease. In the present study w e investigated several aspects of the mechanisms of action of this imm unomodulator. We found that linomide can inhibit acute EAE even when g iven as pretreatment, prior to induction of disease (days - 10 to 0). This inhibitory effect was reversed by adoptive transfer of naive sple en cells. A short course (7 days) of linomide treatment also inhibited EAE, especially when administered immediately after disease induction . Spleen cells from linomide-treated mice failed to present myelin ant igens to T-cell lines in vitro. The defective antigen presentation was normalized by anti-oxidants such as 2-mercaptoethanol. The proportion of Mac1(+) cells in the spleens of linomide-treated mice was signific antly reduced and macrophage growth was inhibited in long term culture s of spleen cells derived from linomide-treated animals. Our findings suggest that the effect of linomide on EAE may be attributed, at least in part, to inactivation of antigen presenting cells, possibly follow ing a short period of over-stimulation and increased oxidant productio n. This mechanism may play a universal role in the regulation of autoi mmune reactivity and merits further investigation.