Glatiramer acetate in the treatment of multiple sclerosis: emerging concepts regarding its mechanism of action

Abstract

Glatiramer acetate is a synthetic, random copolymer widely used as a first-line agent for the treatment of relapsing-remitting multiple sclerosis (MS). While earlier studies primarily attributed its clinical effect to a shift in the cytokine secretion of CD4+ T helper (T(h)) cells, growing evidence in MS and its animal model, experimental autoimmune encephalomyelitis (EAE), suggests that glatiramer acetate treatment is associated with a broader immunomodulatory effect on cells of both the innate and adaptive immune system. To date, glatiramer acetate-mediated modulation of antigen-presenting cells (APC) such as monocytes and dendritic cells, CD4+ T(h) cells, CD8+ T cells, Foxp3+ regulatory T cells and antibody production by plasma cells have been reported; in addition, most recent investigations indicate that glatiramer acetate treatment may also promote regulatory B-cell properties. Experimental evidence suggests that, among these diverse effects, a fostering interplay between anti-inflammatory T-cell populations and regulatory type II APC may be the central axis in glatiramer acetate-mediated immune modulation of CNS autoimmune disease. Besides altering inflammatory processes, glatiramer acetate could exert direct neuroprotective and/or neuroregenerative properties, which could be of relevance for the treatment of MS, but even more so for primarily neurodegenerative disorders, such as Alzheimer's or Parkinson's disease. In this review, we provide a comprehensive and critical overview of established and recent findings aiming to elucidate the complex mechanism of action of glatiramer acetate.

Fig. 1

Glatiramer acetate (GA) mediates pleiotropic immunomodulatory effects. GA treatment promotes development of anti-inflammatory type II antigen presenting cells (APC) predominantly producing interleukin (IL)-10 and transforming growth factor-β (TGFβ). Upon encounter of naïve CD4+ T cells, type II APC deviate T-cell differentiation towards preferential development of T helper (T_h)-2 cells and Foxp3+ regulatory T cells (T_reg). Type II APC and T_h2/T_reg cells may facilitate each other’s development in a positive feedback mechanism, as T cell-derived anti-inflammatory cytokines may in return foster type II differentiation of APC. GA-promoted anti-inflammatory CD4+ T cells may cross the blood-brain- barrier (BBB) and are thought to be locally reactivated within the CNS. In response, these cells may secrete anti-inflammatory cytokines and neurotrophic factors and dampen neighbouring inflammation (‘bystander suppression’). Another feedback loop between APC and T cells may develop within the CNS itself, as T cell-derived cytokines could also promote type II differentiation of resident or recruited CNS APC. In addition, GA can bind to MHC molecules and may thereby compete with myelin antigens (Ag) for their presentation to T cells. Furthermore, GA treatment is associated with induction of GA-reactive CD8+ T cells and most recent findings indicate that GA may also exert an immunomodulatory effect on B cells promoting secretion of anti-inflammatory cytokines. The in vivo function of GA-affected CD8 cells and B cells, and whether these cells may enter the CNS, remains to be determined. co-stim = costimulatory; TCR= T cell receptor; TNF = tumour necrosis factor; ? indicates assumed mechanism; ↓ indicates decrease.