EFFECTIVE TREATMENT OF MODELS OF MULTIPLE-SCLEROSIS BY MATRIX METALLOPROTEINASE INHIBITORS

The proinflammatory Th1 cytokine, tumor necrosis factor-alpha (TNF alp ha), the cell death signaling molecule FasL, and several extracellular matrix degrading metalloproteinases have been implicated in the patho genesis of multiple sclerosis (MS). The latter enzymes, as web as TNF alpha-converting enzyme and FaL-converting enzyme, can be blocked by m atrix metalloproteinase inhibitors (MMPIs). In this study, we show tha t a potent MMPI was clinically effective in an animal model for MS, ex perimental autoimmune encephalomyelitis (EAE) in the SJL/J mouse. Effi cacy was remarkable, as indicated by blocking and reversal of acute di sease and reduced number of relapses and diminished mean cumulative di sease score in chronic relapsing animals. Also, demyelination and glia l scarring were significantly decreased in MMPI-treated mice with chro nic relapsing EAE, as was central nervous system gene expression for T NF alpha. and FaL. It is interesting that expression of the beneficial cytokine interleukin-4 (IL-4) was increased, and IL-4 was expressed o n glial cells. The relevance of these compounds for MS was underscored by their ability to specifically inhibit TNF alpha shedding and cytot oxicity of myelin-autoreactive human cytotoxic CD4(+) T-cell clones. T his is the first report to show a positive effect by MMPIs on chronic relapsing EAE, its central nervous system cytokine profile, and on TNF alpha shedding by human myelin-autoreactive T cells.