Mechanism of action of glatiramer acetate in multiple sclerosis and its potential for the development of new applications

Abstract

Glatiramer acetate (GA, Copaxone, Copolymer 1) is an approved drug for the treatment of multiple sclerosis and is highly effective in the suppression of experimental autoimmune encephalomyelitis in various species. The mode of action of GA is by initial strong promiscuous binding to MHC molecules and consequent competition with various myelin antigens for their presentation to T cells. A further aspect of its action is potent induction of specific suppressor cells of the T helper 2 (Th2) type that migrate to the brain and lead to in situ bystander suppression. Furthermore, the GA-specific cells in the brain express the antiinflammatory cytokines IL-10 and transforming growth factor ␤, in addition to brain-derived neurotrophic factor, whereas they do not express IFN-␥. Based on this immunomodulatory mode of action, we explored the potential of GA for two other applications: prevention of graft rejection and amelioration of inflammatory bowel diseases. GA was effective in amelioration of graft rejection in two systems by prolongation of skin graft survival and inhibition of functional deterioration of thyroid grafts, across minor and major histocompatibility barriers. In all transplantation systems GA treatment inhibited the detrimental secretion of Th1 inflammatory cytokines and induced beneficial Th2͞3 antiinflammatory response. GA was effective also in combination with low-dose immunosuppressive drugs. Inflammatory bowel diseases are characterized by detrimental imbalanced proinflammatory immune reactivity in the gut. GA significantly suppressed the various manifestations of trinitrobenzene sulfonic acid-induced colitis, including mortality, weight loss, and macroscopic and microscopic colonic damage. GA suppressed local lymphocyte proliferations and tumor necrosis factor ␣ detrimental secretion but induced transforming growth factor ␤, thus confirming the involvement of Th1 to Th2 shift in GA mode of action.

Glatiramer acetate increases IL-1 receptor antagonist but decreases T cell-induced IL-1β in human monocytes and multiple sclerosis

“…These results suggest that GA might be useful in autoimmune diseases other than MS, as suggested by its beneficial effect in animal models of autoimmune diseases such as uveoretinitis (25) and inflammatory bowel disease (26), and graft rejection (27), whereas its efficacy has not been demonstrated in animal models of systemic lupus erythematosus (28) and collagen-induced arthritis (29).…”

Mechanism of Action of Glatiramer Acetate in Treatment of Multiple Sclerosis

“…The concept of an antigen-nonspecific effect of GA is further supported by the fact that GA treatment has been shown to be clinically beneficial in other models of autoimmune or inflammatory conditions, such as arthritis, uveoretinitis, 55 inflammatory bowel disease, 56 and graft rejection. 57 Although T cells might not be the primary target of GA, they are most likely the effector cells of GA-mediated immune modulation. Deficiencies in regulatory T cells have been associated with MS pathogenesis 38 and GA-mediated restoration of T-cell regulation correlates with clinical benefit.…”

Glatiramer acetate triggers PI3Kδ/Akt and MEK/ERK pathways to induce IL-1 receptor antagonist in human monocytes

“…Nevertheless, increasing number of reports indicate that GA treatment also exerts immunomodulatory activity on cells of the myelo-monocytic lineage, i.e., monocytes/ macrophages and dendritic cells (15)(16)(17)(18)(19)(20)(21)(22)(23). These observations suggest that GA might be useful in autoimmune diseases other than MS, as suggested by its beneficial effect in animal models of uveoretinitis (24), inflammatory bowel disease (25), and graft rejection (26).…”