myelin-basic-protein and lisofylline

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.

Topics: Adoptive Transfer; Animals; Anti-Inflammatory Agents, Non-Steroidal; Autoimmune Diseases; Cell Differentiation; Drug Evaluation, Preclinical; Encephalomyelitis, Autoimmune, Experimental; Female; Gene Expression Regulation; Immunization; Interferon-gamma; Interleukin-12; Interleukin-4; Lymphocyte Activation; Mice; Mice, Inbred Strains; Myelin Basic Protein; Pentoxifylline; Recombinant Proteins; Severity of Illness Index; Signal Transduction; Th1 Cells