THE LENGTH OF TREATMENT DETERMINES WHETHER IFN-BETA PREVENTS OR AGGRAVATES EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS IN LEWIS RATS

The mechanism of action underlying the beneficial effect of IFN-beta i n multiple sclerosis (MS) is not understood. To date, little informati on is available on the effects of IFN-beta in experimental autoimmune encephalomyelitis (EAE), the animal correlate of the human disease MS. Therefore, we investigated the effects of recombinant rat IFN-beta (r rIFN-beta) on EAE in Lewis rats with emphasis on a treatment regimen d uring the paralytic phase of the disease. The results indicated that r rIFN-beta dose-dependently inhibited disease activity with complete pr evention at a s.c. dose of 300,000 U/day, provided that treatment was continued for 3 wk. Discontinuation of treatment on day 17 postimmuniz ation resulted in a protracted and relapsing disease course with stron gly enhanced clinical severity. Detailed immunohistology of central ne rvous system (CNS) tissue of protected animals revealed an almost comp lete absence of CNS lesions and a >90% reduction in the number of infi ltrating leukocytes. Accordingly, isolation of mononuclear cells from spinal cord tissue of successfully treated EAE rats revealed a reducti on of approximately 95% in the number of cells that produce IFN-gamma in response to the encephalitogenic peptide MBP(63-83). Furthermore, r rIFN-beta significantly enhanced serum corticosterone levels, which sh owed an inverse relationship with disease activity. We show that rrIFN -beta can have both beneficial and detrimental effects on disease acti vity dependent on the timing and the duration of treatment. Beneficial effects on EAE are associated with inhibition of the extravasation of blood-derived mononuclear cells in the CNS.