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Effective treatment of models of multiple sclerosis by matrix metalloproteinase inhibitors
Author(s) -
Liedtke Wolfgang,
Cannella Barbara,
Mazzaccaro Richard J.,
Clements John M.,
Miller Karen M.,
Wucherpfenning Kai W.,
Gearing Andrew J. H.,
Raine Cedric S.
Publication year - 1998
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.410440110
Subject(s) - multiple sclerosis , immunology , tumor necrosis factor alpha , experimental autoimmune encephalomyelitis , proinflammatory cytokine , cytokine , fas ligand , myelin , medicine , matrix metalloproteinase , encephalomyelitis , central nervous system , biology , inflammation , endocrinology , programmed cell death , apoptosis , biochemistry
The proinflammatory Th1 cytokine, tumor necrosis factor‐α (TNFα), the cell death signaling molecule FasL, and several extracellular matrix degrading metalloproteinases have been implicated in the pathogenesis of multiple sclerosis (MS). The latter enzymes, as well as TNFα‐converting enzyme and FasL‐converting enzyme, can be blocked by matrix metalloproteinase inhibitors (MMPIs). In this study, we show that a potent MMPI was clinically effective in an animal model for MS, experimental autoimmune encephalomyelitis (EAE) in the SJL/J mouse. Efficacy was remarkable, as indicated by blocking and reversal of acute disease and reduced number of relapses and diminished mean cumulative disease score in chronic relapsing animals. Also, demyelination and glial scarring were significantly decreased in MMPI‐treated mice with chronic relapsing EAE, as was central nervous system gene expression for TNFα and fasL. It is interesting that expression of the beneficial cytokine interleukin‐4 (IL‐4) was increased, and IL‐4 was expressed on glial cells. The relevance of these compounds for MS was underscored by their ability to specifically inhibit TNFα shedding and cytotoxicity of myelin‐autoreactive human cytotoxic CD4 + T‐cell clones. This is the first report to show a positive effect by MMPIs on chronic relapsing EAE, its central nervous system cytokine profile, and on TNFα shedding by human myelin‐autoreactive T cells.