Glatiramer acetate: mechanisms of action in multiple sclerosis.
Glatiramer acetate (GA), formerly known as copolymer 1, is a mixture of synthetic polypeptides composed of four amino acids resembling the myelin basic protein (MSP). GA has been shown to be highly effective in preventing and suppressing experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS). Therefore, it was tested in several clinical studies and so approved for the immunomodulatory treatment of relapsing-type MS. In contrast to other immunomodulatory MS therapies, GA has a distinct mechanism of action: GA demonstrates an initial strong promiscuous binding to major histocompatibility complex molecules and consequent competition with various (myelin) antigens for their presentation to T cells. In addition, antigen-based therapy generating a GA-specific immune response seems to be the prerequisite for GA therapy. GA treatment induces an in vivo change of the frequency, cytokine secretion pattern and the effector function of GA-specific CD4+ and CD8+ T cells, probably by affecting the properties of antigen-presenting cells such as monocytes and dendritic cells. As demonstrated extensively in animal experiments, GA-specific, mostly, T helper 2 cells migrate to the brain and lead to in situ bystander suppression of the inflammatory process in the brain. Furthermore, GA-specific cells in the brain express neurotrophic factors like the brain-derived neurotrophic factor (BDNF) in addition to anti-inflammatory T helper 2-like cytokines. This might help tip the balance in favor of more beneficial influences because there is a complex interplay between detrimental and beneficial factors and mediators in the inflammatory milieu of MS lesions.
Ziemssen
Tjalf
T
Multiple Sclerosis Center Dresden, Neurological University Clinic Dresden University of Technology, Dresden 01307, Germany.
Schrempf
Wiebke
W
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D004195:Disease Models, Animal; D000068717:Glatiramer Acetate; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D008213:Lymphocyte Activation / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000473:pathology; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*
D019208:Brain-Derived Neurotrophic Factor; D007166:Immunosuppressive Agents; D010455:Peptides; D000068717:Glatiramer Acetate