Immunomodulation neuroprotection and remyelination – The fundamental therapeutic effects of glatiramer acetate: A critical review

• Multiple sclerosis is a heterogeneous disease with various patterns of tissue damage.
• MS therapies aim to restrain the pathological processes and enhance protective routes.
• GA induces deviation from pro-inflammatory to anti-inflammatory immune pathways.
• In addition to immunomodulation GA promotes neuroprotective repair processes.
• GA affects pathologies such as immune rejection and inflammatory bowel disease.

Multiple sclerosis (MS) is a multifaceted heterogeneous disease with various patterns of tissue damage. In addition to inflammation and demyelination, widespread axonal and neuronal pathologies are central components of this disease. MS therapies aim to restrain the pathological processes, enhance protective mechanisms, and prevent disease progression. The amino acid copolymer, glatiramer acetate (GA, Copaxone), an approved treatment for MS, has a unique mode of action. Evidence from the animal model experimental autoimmune encephalomyelitis (EAE) and from MS patients indicates that GA affects various levels of the innate and the adaptive immune response, inducing deviation from the pro-inflammatory to the anti-inflammatory pathways. This includes competition for the binding of antigen presenting cells, driving dendritic cells, monocytes, and B-cells towards anti-inflammatory responses, induction of Th2/3 and T-regulatory cells, and downregulating of both Th1 and Th-17 cells. The immune cells induced by GA reach the inflamed disease organ and secrete in situ anti-inflammatory cytokines alleviating the pathological processes. Furthermore, cumulative findings have revealed that in addition to its immunomodulatory activities GA promotes neuroprotective repair processes such as neurotrophic factors secretion and remyelination. This review aims to provide a comprehensive overview on the diverse mechanism of action of GA in EAE/MS, in particular on the in situ effect of GA and its ability to generate neuroprotection and repair in the CNS. In view of its immunomodulatory activity, the beneficial effects of GA in various models of additional autoimmune related pathologies, such as immune rejection and inflammatory bowel disease (IBD), are also presented.