DISCONTINUATION OF TREATMENT WITH IFN-BETA LEADS TO EXACERBATION OF EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS IN LEWIS RATS - RAPID REVERSAL OF THE ANTIPROLIFERATIVE ACTIVITY OF IFN-BETA AND EXCESSIVE EXPANSION OF AUTOREACTIVE T-CELLS AS DISEASE PROMOTING MECHANISMS

IFN-beta has recently been shown to exert remarkable beneficial effect s on disease development in patients with early stage relapsing-remitt ing MS. The specific immune mechanism(s) by which IFN-beta ameliorates this human demyelinating disease is at present undefined. One potenti al mechanism may reside in the antiproliferative activity of IFN-beta which may inhibit the expansion of autoaggressive T cells thereby limi ting disease progression. In the present study we investigated whether the administration Of recombinant rat IFN-beta (rrIFN-beta) to Lewis rats with actively induced experimental autoimmune encephalomyelitis ( EAE) inhibits the expansion of encephalitogenic T cells in lymphoid or gans and as such may contribute to suppression of disease activity in this widely used animal model for MS. Our data show that daily adminis trations of greater than or equal to 3 x 10(5) u rrIFN-beta to EAE rat s, starting two days before MBP sensitization and continued for 10 day s led to a dramatic and dose-dependent reduction in encephalitogenic T cells in both spleen and inguinal lymph nodes at day 8 post-immunizat ion (p.i.). However, the rrIFN-beta-mediated reduction in effector T c ells did not ameliorate paralytic disease as expected but significantl y enhanced the severity of EAE. Analyses of lymphoid organs in the rem ission phase of EAE revealed strongly elevated numbers of encephalitog enic T cells in rrIFN-beta-treated versus control rats suggesting a ra pid reversal of EAE antiproliferative action of rrIFN-beta followed by an overshoot in the subsequent expansion of these effector T cells. I n conformity with higher numbers of encephalitogenic T cells and worse ning of disease, animals also showed significantly greater perivascula r inflammation in the CNS, The relevance of our findings in relation t o the beneficial effects of IFN-beta in MS is discussed. (C) 1998 Else vier Science B.V.