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Effective treatment of models of multiple sclerosis by matrix metalloproteinase inhibitors
W Liedtke1, B Cannella, R J Mazzaccaro
1Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA.
Abstract:
The proinflammatory Th1 cytokine, tumor necrosis factor-alpha (TNF alpha), 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 TNF alpha-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 TNF alpha 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 TNF alpha 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 TNF alpha shedding by human myelin-autoreactive T cells.
Insights
Matrix metalloproteinase inhibitors (MMPIs) effectively treated experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS). MMPIs reduced disease severity, demyelination, and glial scarring, offering a promising therapeutic avenue for MS.
Area of Science:
- Neuroimmunology
- Pharmacology
Background:
- Tumor necrosis factor-alpha (TNF alpha), FasL, and matrix metalloproteinases are implicated in multiple sclerosis (MS) pathogenesis.
- Matrix metalloproteinase inhibitors (MMPIs) can block these enzymes and their activating enzymes.
Purpose of the Study:
- To evaluate the efficacy of a potent MMPI in an animal model of MS, experimental autoimmune encephalomyelitis (EAE).
- To investigate the effects of MMPIs on disease progression, central nervous system (CNS) cytokine profiles, and T-cell activity in EAE.
Main Methods:
- Administration of a potent MMPI to SJL/J mice with EAE.
- Assessment of clinical disease scores, relapses, demyelination, and glial scarring.
- Analysis of CNS gene expression for TNF alpha, FasL, and IL-4.
- Evaluation of MMPIs' effect on TNF alpha shedding and cytotoxicity of human myelin-autoreactive T-cell clones.
Main Results:
- MMPI treatment significantly blocked and reversed acute EAE.
- Chronic relapsing EAE animals showed reduced relapses, lower cumulative disease scores, decreased demyelination, and less glial scarring.
- CNS gene expression of TNF alpha and FasL was reduced, while IL-4 expression increased, particularly on glial cells.
- MMPIs specifically inhibited TNF alpha shedding and cytotoxicity of human myelin-autoreactive CD4+ T-cell clones.
Conclusions:
- MMPIs demonstrate significant therapeutic potential for multiple sclerosis (MS) by impacting key pathological pathways.
- This study provides the first evidence of MMPI efficacy in chronic relapsing EAE, including modulation of CNS cytokine profiles and T-cell responses.