Prevention of experimental autoimmune encephalomyelitis by antibodies against interleukin 12

Abstract

Experimental allergic encephalomyelitis (EAE) is an autoimmune disease of the central nervous system that can be transferred to naive mice via CD4+ T cells isolated from appropriately immunized mice. We have evaluated the effects of recombinant murine interleukin 12 (rmi1:12), a potent inducer of interferon γ(IFN-γ) and promoter ofThl T cell development, on the course of adoptively transferred EAE. The transfer of lymph node cells (LNC) isolated from proteolipid protein (PLP)-primed animals and stimulated in vitro with PLP to naive mice resulted in a progressive paralytic disease culminating in complete hind limb paralysis in the majority of the recipients. When mice were injected with LNC that had been stimulated in vitro with PLP in the presence of rmi1:12, the subsequent course of disease was more severe and prolonged. The addition of rmlL-12 during the in vitro stimulation with PLP resulted in a 10-fold increase in IFN-γ and a 2-fold increase in tumor necrosis factor (TNF) α in the supernatants, relative to LNC stimulated with PLP alone. However, neutralization of IFN-3, or TNF-α in vitro with specific antibodies did not abrogate the ability of rmlL-12 to exacerbate the subsequent disease. Similarly, mice treated with rmi1:12 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 an antibody to murine I1:12 after cell transfer completely prevented paralysis, with only 40% of the mice developing mild disease. These results demonstrate that in vitro stimulation of antigen primed LNC with PLP and rmlb12 enhances their subsequent encephalitogenicity. Furthermore, inhibition of endogenous IL-12 in vivo after LNC transfer prevented paralysis, suggesting that endogenous 11:12 plays a pivotal role in the pathogenesis of this model of autoimmune disease. © 1995, Rockefeller University Press., All rights reserved.