Probing cytokines, chemokines and matrix metalloproteinases towards better immunotherapies of multiple sclerosis

Abstract

Multiple sclerosis (MS) is an autoimmune disease with a spectrum of clinical evolutions. We here summarize recent insights into the neuroinflammatory processes of demyelination, vascular cuffing, destruction of the blood brain barrier (BBB), neuronal toxicity and the ensuing (re)activation of autoreactive lymphocytes. Translation of these processes in molecular terms indicates that cytokines, including interferons, ligands of the tumor necrosis factor receptor family and interleukins, and also chemokines and matrix metalloproteinases play pivotal roles in MS. This not only helps to understand disease mechanisms in the central nervous system of affected patients, but also forms a solid scientific basis to improve present therapies. Treatment of MS with parenterally administered anti-inflammatory agents may be improved, based on present knowledge and new insights obtained with animal models. Such innovations include better use of knowledge about the formulation, administration, turnover and glycosylation of interferon-β (IFN-β), combinations of IFN-β with inhibitors of IFN-β-degrading proteinases in MS, and new ways to diminish vascular cuffs and the transmigration of leukocytes across the two basement membranes of the BBB. Novel molecules interfering with matrix metalloproteinases and chemokines, such as EMMPRIN, COAM and monoclonal antibodies are currently being investigated, demonstrating continued efforts to find new drugs for MS treatment.