Glatiramer acetate: Mechanisms of action in multiple sclerosis

Glatiramer acetate (GA) is a mixture of synthetic polypeptides composed of four amino acids resembling myelin basic protein (MBP). GA has been shown to be effective in preventing and suppressing experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis. It was tested in several clinical studies and approved for the immunomodulatory treatment of relapsing-type MS in 1996. Glatiramer acetate demonstrates a strong promiscuous binding to major histocompatibility complex molecules and inhibits the T cell response to several myelin antigens. In addition, it was shown to act as a T cell receptor antagonist for the 82-100 MBP epitope. Glatiramer acetate treatment causes in vivo changes of the frequency, cytokine secretion pattern and effector function of GA-specific T cells. It was shown to induce GA-specific regulatory CD4(+) and CD8(+) T cells and a TH1-TH2 shift with consecutively increased secretion of antiinflammatory cytokines. GA-specific TH2 cells are able to migrate across the blood-brain barrier and cause in situ bystander suppression of autoaggressive TH1 T cells. In addition glatiramer acetate was demonstrated to influence antigen presenting cells (APC) such as monocytes and dendritic cells. Furthermore secretion of neurotrophic factors with potential neuroprotective effects was shown. (c) 2007 Elsevier B.V. All rights reserved.