in MS. GA has been shown to induce a deviation from a “pro- inﬂammatory” Th1 state in T cells to an “anti-inﬂammatory” Th2 state, both in vitro and in vivo. Thus, when dendritic cells (DC), which are highly efﬁcient APC, are treated with GA, secretion of IL-12, a cytokine which causes Th-1 differentia- tion of naïve Th cells, decreases in a dose-response manner. Naïve Th cells exposed to GA-treated DCs thus differentiate into Th-2 cells (Vieira et al 2003). EAE is suppressed in mice treated with Th-2 GA-induced T cells (Aharoni et al 1997). In a study of 8 MS patients treated with GA, GA-speciﬁc T cells were deviated to a Th-2 polarization (Qin et al 2000). This has been seen in other studies ( Duda et al 2000; Neuhaus et al 2000; Chen et al 2001). There are other mechanisms which may also contribute to the therapeutic effect of GA in MS. As stated above, APCs activate antigen-speciﬁc T cells of either a Th1 or Th2 phenotype, depending on whether the APC has an M1 or M2 phenotype (Kalinski et al 1999). It has been shown that GA inﬂuences APC towards an M1 (IL-12 secreting) or M2 (IL-10 secreting) phenotype (Hussien et al 2001; Farina et al 2005; Kim et al 2004; Weber et al 2004) which may in turn inﬂuence the resultant proportion of Th1 and Th2 lym- phocytes reactive to GA and cross reacting myelin antigen speciﬁc T cells. There are reports of changes in function of monocytes/macrophages/microglia and dendritic cells in patients treated with GA (Balabanov et al 2001; Hussien et al 2001; Weber et al 2004) The lymphocytes of normal individuals and GA naive patients with MS respond to GA in vitro with a vigorous proliferative response whereas patients treated with GA lose this response. The loss of a proliferative response seems to be due to both clonal deletion and clonal anergy (Ragheb et al 2001). This would reduce the number of potentially myelin reactive cells that also recognize GA which would be of po- tential beneﬁt. Finally there is evidence that GA also can bind to MHC class 1 but not CD and thus inﬂuence CD8 (cytotoxic and immunosuppressive) T cells (Karandikar et al 2002). Finally, as mentioned above, GA-speciﬁc T cells may have a neuroprotectant action by elaborating neurotrophic factors in addition to anti-inﬂammatory cytokines. Activated T cells speciﬁc for myelin antigens have been shown to produce brain-derived neurotrophic factor (BDNF) (Kerschensteiner et al 1999) In a study of T cell lines obtained from GA-treated MS patients, 14% of the GA-reactive T cells (all Th-2) and smaller proportions of MBP- and tetanus toxoid (TT)-reac- tive T cells were found to secrete BDNF (Kerschensteiner et al 1999; Chen et al 2003). GA-speciﬁc Th2 and Th1 cells both can secrete BDNF (Kipnis et al 2000; Ziemssen et al Neuropsychiatric Disease and Treatment 2007:3(2) Glatiramer acetate 2002) as well as other neurotrophic factors although Th2 cells seem to secrete higher levels of these factors than Th1 cells. In addition both MBP- and GA-reactive T cells make nerve growth factor (NGF) and neurotrophin 4/5 (NT-4/5) (Kipnis et al 2000). It is of interest that in both GA treated animals and naïve animals that receive GA reactive lymphocytes, neuroprotection can be demonstrated in both EAE (Aharoni et al 2000) as well as in models of optic nerve trauma (Kipnis et al 2000), retinal cell damage from glaucoma (Bakalash et al 2005) and degenerative diseases such as amyotrophic lateral sclerosis (Angelov et al 2003) and Parkinson’s disease (Benner et al 2004). More recently, glatiramer has shown hints of efﬁcacy in a mouse model of Alzheimer’s disease (Frenkel et al 2005), as well as some neuroprotectant effect in organophosphate neurotoxicity (Schori et al 2005). However, whether the currently used regimen of GA in MS patients leads to the presence of BDNF- secreting T cells in the brain is unknown. Conclusion Glatiramer acetate is a drug with beneﬁcial effects on the course of multiple sclerosis, reducing both relapse frequency and probably accumulation of deﬁcit over time. The drug also has beneﬁcial effects on MRI disease activity. Although the mechanisms of action are not known in detail, it is clear that they are multifactorial. There is a down-regulation of inﬂammatory activity in the MS brain, as well as a neuroprotectant effect. In fact, the elaboration of BDNF by T cells may be useful in other disease states in which neurodegeneration plays a role. References Abramsky O, Teitelbaum D, Arnon R. 1977. 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