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The Journal of Immunology, 1998, 161: 7015-7022.
Copyright © 1998 by The American Association of Immunologists

Prevention of Experimental Allergic Encephalomyelitis via Inhibition of IL-12 Signaling and IL-12-Mediated Th1 Differentiation: An Effect of the Novel Anti-Inflammatory Drug Lisofylline1

John J. Bright2,*, Caigan Du2,*, Michael Coon{dagger}, Subramaniam Sriram* and Stephen J. Klaus3,{dagger}

* Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37212; and {dagger} Cell Therapeutics, Inc., Seattle, WA 98119

Experimental allergic encephalomyelitis (EAE) is an inflammatory, CD4+ Th1-mediated autoimmune disease, which serves as a model for multiple sclerosis. We examined the effect of a novel anti-inflammatory drug, lisofylline (LSF), on EAE induced either by injection of mouse spinal cord homogenate or following transfer of myelin basic protein-reactive T cells. Orally administered LSF significantly inhibited EAE in both cases, decreasing peak clinical scores by >70% and >80%, respectively. In addition, analysis of representative spinal cord sections from LSF-treated mice showed complete lack of demyelination and lymphocyte infiltration. The reduction in EAE correlated with the inhibition of Th1 differentiation by LSF in vivo, as indicated by a reduction in T cell IFN-{gamma} production ex vivo after Ag restimulation. The inhibition of Th1 differentiation in vivo is consistent with a block in IL-12 receptor signaling, because LSF blocked IL-12-driven Th1 differentiation and T cell proliferation in vitro, yet had no effect on IL-12 secretion from APCs ex vivo or in vitro.




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