PREVENTION OF EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS BY ANTIBODIESAGAINST INTERLEUKIN-12

Experimental allergic encephalomyelitis (EAE) is an autoimmune disease of the central nervous system that can be transferred to naive mice v ia CD4(+) T cells isolated from appropriately immunized mice. We have evaluated the effects of recombinant murine interleukin 12 (rmIL-12), a potent inducer of interferon gamma (IFN-gamma) and promoter of Th1 T cell development, on the course of adoptively transferred EAE. The tr ansfer of lymph node cells (LNC) isolated from proteolipid protein (PL P)-primed animals and stimulated in vitro with PLP to naive mice resul ted in a progressive paralytic disease culminating in complete hind li mb paralysis in the majority of the recipients. When mice were injecte d with LNC that had been stimulated in vitro with PLP in the presence of rmIL-12, the subsequent course of disease was more severe and prolo nged. The addition of rmlL-12 during the in vitro stimulation with PLP resulted in a 10-fold increase in IFN-gamma and a 2-fold increase in tumor necrosis factor (TNF) alpha in the supernatants, relative to LNC stimulated with PLP alone. However, neutralization of IFN-gamma or TN F-alpha in vitro with specific antibodies did not abrogate the ability of rmIL-12 to exacerbate the subsequent disease. Similarly, mice trea ted with rmIL-12 in vivo after the transfer of antigen-stimulated LNC developed a more severe and prolonged course of disease compared with vehicle-treated control animals. In contrast, treatment of mice with a n antibody to murine IL-12 after cell transfer completely prevented pa ralysis, with only 40% of the mice developing mild disease. These resu lts demonstrate that in vitro stimulation of antigen primed LNC with P LP and rmIL-12 enhances their subsequent encephalitogenicity. Furtherm ore, inhibition of endogenous IL-12 in vivo after LNC transfer prevent ed paralysis, suggesting that endogenous IL-12 plays a pivotal role in the pathogenesis of this model of autoimmune disease.