A critical review of the fundamental therapeutic effects of glatiramer acetate
This article reviews the history of Glatiramer Acetate (GA), from its discovery until now. GA is the first, and so far the only, therapeutic agent to have a copolymer as its active ingredient. GA at a daily subcutaneous dose of 20 mg has been found to alter the natural history of RRMS by reducing the relapse rate and affecting disability. These consequences are consistent with magnetic resonance imaging (MRI) findings from various clinical centres and it is, currently, one of the most widely prescribed first-line treatments for RRMS.
Nevertheless, over the last four decades, findings obtained from multiple in vitro and in vivo systems have clarified the immunological mechanism of action of GA. Furthermore, recent studies have revealed neuroprotective repair consequences of GA treatment in the central nervous system (CNS). GA induces a broad immunomodulatory effect on various subsets of the immune system. The initial prerequisite step is the binding of GA to major histocompatibility (MHC) class II molecules. This competitive binding for the histocompatibility molecules can prevent the presentation of other antigens and hinder their T-cell activation. Several groups have demonstrated that GA induces generalized alterations of various types of APCs, such as dendritic cells and monocytes, so that they preferentially stimulate protective anti-inflammatory responses. Indeed, dendritic cells from GA-treated MS patients produce less TNF-α, less IL-12, and more IL-10, compared to those of untreated patients. GA induces a broad inhibitory effect on monocyte reactivity, and promotes the development of anti-inflammatory type II monocytes characterized by increased secretion of IL-10 and TGF-β, as well as by decreased production of IL-12 and TNF.
Most studies attribute the primary mechanism of GA activity to its ability to shift the T-cell response from the pro-inflammatory to the anti-inflammatory pathway. A shift from a pro-inflammatory Th1-biased cytokine profile towards an anti-inflammatory Th2-biased profile was also observed in GA-treated MS patients, indicating that such cells are involved in the therapeutic effect of GA in MS. GA treatment generates a broad immunomodulatory effect on various subsets of the immune system. This includes competition for the binding of antigen presenting cells, steering 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. It has been shown that GA has a neuroprotective effects in MS and EAE. The initial indication for neuroprotective activity was the ability of GA-induced cells to secrete brain derived neurotrophic factor (BDNF). This was demonstrated for murine GA-specific T-cells originating from the periphery or the CNS, as well as for human T- cell lines. Members of the neurotrophin family such as BDNF, NT-3 and NT-4 are important regulators of neuronal function and survival. They were shown to promote axonal outgrowth, remyelination and regeneration. Furthermore, GA treatment accelerates postnatal myelinogenesis in the developing nervous system under non-pathological conditions supporting the notion that developmental as well as repair process in the CNS can be up-regulated by therapy.
: Aharoni R.
Source: J Autoimmun. 2014 Jun 13. pii: S0896-8411(14)00094-8. doi: 10.1016/j.jaut.2014.05.005. [Epub ahead of print]
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