Glatiramer for MS Figure 1 A simplified diagrammatic representation of the immunopharmacology of GA in MS therapeutics. The Pre-r x portion of the panel emphasizes the baseline state in MS with CD4+ Th1 myelin antigen-reactive cells being activated by systemic antigen processing cells, including macrophages, that present foreign antigens that are myelin-like (‘myelin’ Ag) in the context of surface MHC to TCr ; invoking the concept of molecular mimicry. Stimulated CD4+ Th1 ‘myelin’ Ag-reactive cells secrete a number of pro-inflammatory cytokines (iL-2, iFN-γ, TNF-α, and LT). w ith GA therapy, GA may displace some ‘myelin’ Ag. More importantly, on presentation and stimulation of GA and ‘myelin’ Ag-reactive CD4+ Th1 cells, GA silences cross-reacting CD4+ Th1 ‘myelin’ Ag-reactive cells through anergy, apoptosis, or antigen-specific mechanisms. Concomitantly, GA stimulates and expands a population of GA-reactive CD4+ Th1 cells (dark grey curved arrows). w ith continued therapy the net result is a reduced proportion of CD4+ Th1 and an increased proportion of GA and ‘myelin’ cross-reactive CD4+ Th2 cells. w hen these GA and ‘myelin’ cross-reactive CD4+ Th2 cells gain access to the CNS by trafficking across the blood–brain barrier, they are re-stimulated by true myelin Ags processed and presented by microglia, a brain-resident macrophage. On re-stimulation, the GA-reactive CD4+ Th2 cells secrete anti-inflammatory cytokines to inhibit ‘myelin’ Ag-reactive CD4+ Th1 cells within the CNS and also secret topic factors, such as BDNF that may facilitate neuronal survival (light grey curved arrow). r eproduced from w olinsky JS 2004a. Glatiramer acetate for the treatment of multiple sclerosis. Expert Opin Pharmacother, 5:875–91. Copyright © 2004 with permission from Ashley Publications. Abbreviations: Ag, antibody; BDNF, brain-derived neutrophic factor; GA, glatiramer acetate; iFN, interferon; LT, leukotriene; MHC, major histocompatibility complex; MS, multiple sclerosis; r x, treatment; TCr , T cell receptor; TNF, tumor necrosis factor. axonal degeneration, and via support of oligodendrocytes as BDNF. Evidence has shown that locally activated GA- and remyelination. Studies have shown BDNF’s ability to reactive Th2 cells produce BDNF ( Ziemssen et al 2002). In rescue degenerating neurons by inducing axonal outgrowth, GA-treated EAE-induced mice, brain regions demonstrating remyelination, and regeneration (Gravel et al 1997; Yan et high populations of GA-specific T cells also had high levels al 2002). In situ data have demonstrated increased BDNF expression from immune cells isolated from MS lesions (Kerschensteiner et al 2003) and studies on interferon-β- treated MS patients show higher BDNF production compared with healthy volunteers (Petereit et al 2003). Given these of BDNF and Th2 anti-inflammatory cytokines (Aharoni et al 2003). Another study found a reduced level of BDNF in the serum and CSF of RRMS patients which was reversed after therapy with GA (Azoulay et al 2005). GA antibodies observations, BDNF may be a potent neurotrophic factor with Neutralizing antibodies to interferons is associated with the ability to greatly impact neuronal repair and regrowth worsening clinical efficacy and MRI parameters. Although (Thoenen 1995; Barde 1997). patients treated with GA develop binding antibodies, there It is possible that GA may also mediate a neuroprotective is no evidence that the antibodies influence the therapeutic role via increased production of neurotrophic factors such effect of the drug (Farina et al 2002). international Journal of Nanomedicine 2006:1(3) 285