The goal of these studies is to develop an orally bioavailable compound for the treatment of multiple sclerosis (MS), by defining the pharmacophore of a novel anti-inflammatory compound termed Lisofylline (LSF). MS is a T cell mediated, demyelinating autoimmune disease which leads to paralysis in mostly young adults, and can be mimicked experimentally in a murine model termed Experimental Allergic Encephalomyelitis (EAE). LSF inhibits EAE by preventing T cell differentiation into Th1 type T cells, which secrete proinflammatory cytokines considered critical for the induction of autoimmunity. Although LSF is safe for humans and improves infection and mortality in patients undergoing bone marrow transplantation, it requires intravenous administration because it does not survive first pass metabolism by human liver. Using an in vivo Th1 differentiation assay where LSF also shows efficacy, it is possible to develop a LSF analogue with an identical pharmacophore which resists metabolism by human liver. Developing a LSF analogue which is orally bioavailable to humans is a major advance in the search for a compound with the therapeutic potential for treating MS. LSF will also be used to probe signaling pathways that control Th1 differentiation, to provide a better understanding of the molecular events that regulate inflammation.
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| Coon, M E; Diegel, M; Leshinsky, N et al. (1999) Selective pharmacologic inhibition of murine and human IL-12-dependent Th1 differentiation and IL-12 signaling. J Immunol 163:6567-74 |
