The influence of glatiramer acetate on Th17-immune response in multiple sclerosis

Glatiramer acetate (GA) is approved for the treatment of multiple sclerosis (MS). However, the mechanism of action of GA in MS is still unclear. In particular, it is not known whether GA can modulate the pro-inflammatory Th17-type immune response in MS. We investigated the effects of original GA (Copaxone(R), Teva, Israel) and generic GA (Timexone(R), Biocad, Russia) on Th17- and Th1-type cytokine production in vitro in 25 patients with relapsing-remitting MS and 25 healthy subjects. Both original and generic GA at concentrations 50-200 mu g/ml dose-dependently inhibited interleukin-17 and interferon-gamma production by anti-CD3/anti-CD28-activated peripheral blood mononuclear cells from MS patients and healthy subjects. This effect of GA was reproduced using purified CD4(+) T cells, suggesting that GA can directly modulate the functions of Th17 and Th1 cells. At high concentrations (100-200 mu g/ml), GA also suppressed the production of Th17-differentiation cytokines (interleukin-1 beta and interleukin-6) by lipopolysaccharide (LPS)-activated dendritic cells (DCs). These GA/LPS-treated DCs induced lower interleukin-17 and interferon-gamma production by autologous CD4(+) T cells compared to LPS-treated DCs. These data suggest that GA can inhibit Th17-immune response and that this inhibitory effect is preferentially exercised by direct influence of GA on T cells. We also demonstrate a comparable ability of original and generic GA to modulate pro-inflammatory cytokine production.