Tselis et al effectively. This provided a rationale for studying its effect on MS, as described above. Several potential mechanisms of action have been suggested. These are not mutually exclusive, and all prob- ably contribute to the drug’s efﬁcacy. Given the molecular resemblance of some of the components of the drug to frag- ments of myelin basic protein, it is likely that molecular mimicry (in some sense) drives the effects of the drug on the disease process. The postulated steps in the immune reaction to myelin are as follows, in a very oversimpliﬁed version. An activated T cell, sensitive to a myelin antigen (such as myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), myelin associated glycoprotein (MAG) or others) penetrates the blood-brain barrier, and encounters an antigen-presenting cell (APC). The APC presents a peptide fragment from the relevant myelin antigen (perhaps in the process of turnover of myelin in the central nervous system), nestled in the groove of the major histocompatibility class II molecule (MHC-II), to the T cell, along with costimulatory ligands. The T cell receptor engages the peptide fragment nestled in the MHC- II and the appropriate costimulatory ligands on the antigen presenting cell (APC) bind to the coreceptors on the T cell. The APC directs the phenotype of the T cells that are gener- ated, with M1-type APCs stimulating T cells in a T helper-1 (Th1) or “proinﬂammatory” conﬁguration and M2-type APCs promoting Th2 or “anti-inﬂammatory” T cells. In MS, the APCs seem to adopt an M1-phenotype, elaborating IL-12 which activates the T cell into a Th1 state with production of Th1-type cytokines (such as IL-2, IFN-γ, TNFα). TNFα is also elaborated by APCs. These cytokines open up the blood- brain barrier and allow ingress of other cellular and humoral inﬂammatory mediators into the brain, eventually resulting in demyelination and injury to axons. There is strong evidence that in both MS and EAE Ig synthesis and deposition with complement activation contribute to demyelination (Raine et al 1999; Lucchinetti et al 2000). The GA molecule most likely substitutes for the myelin peptide fragment in the APC and exerts its effects from there. The GA molecule is known to inhibit the proliferative T cell response to MBP (Teitelbaum et al 1992). The potential mechanisms of action include the following. (1) The GA molecule binds to the MHC-molecule on the APC so strongly that it displaces fragments of MBP from the APC which would otherwise have been presented to an appropriately sensitized T cell (Fridkis-Hareli et al 1994). This binding occurs equally well with different MHC-II molecules, indicating a certain “promiscuity” 264 in the choice of MHC-II haplotype to be used by GA (Fridkis-Hareli et al 1994). This may be one possible explanation of why GA prevents EAE induced by PLP in mice, although it is not known that GA displaces PLP from the MHC-II molecule (Teitelbaum et al 1996). It is not clear how relevant this mechanism of MBP antigen displacement is, however, since presumably APCs loaded with MBP are present in the brain, and subcutaneously injected GA will not have easy access to them. (2) The GA-MHC-II complex binds to the T cell receptor of the T cell, thus preventing its activation by the MBP- MHC-II complex on the APC. This would cause blockade of T cell receptors by a GA-MHC-II complex competing with an MBP-MHC-II complex. This may not happen centrally, since access of subcutaneously injected GA, complexing with an MHC-II molecule, does not easily have access to APCs located centrally. However, such an effect has been demonstrated in vitro (Aharoni et al 1999). (3) The GA-MHC-II complex binds to the T cell receptor and partially activates the T cell, inducing tolerance by an “altered peptide ligand” mechanism (Aharoni et al 1999). GA thus induces a deviation from a pro-inﬂam- matory Th-1 immune response to an anti-inﬂammatory T helper-2 (Th-2) response, with secretion of the cyto- kines IL-4, IL-5, IL-10, IL-13, and TGF-β, which some investigators consider a Th3 cytokine. Lymphocytes secreting anti-inﬂammatory factors would explain the clinical improvement in animals with EAE who still have inﬂammatory lesions, with the presence of lymphocytes, after treatment (Aharoni et al 2000; Lisak et al 1983). The quantity of anti-inﬂammatory cytokines induced by the cross-reactivity of MBP and GA seems to be at the level of inducing increased cytokine secretion on a per cell basis (Farina et al 2001) rather than by induction of proliferation of lymphocytes. (Burns and Littleﬁeld 1991; Lisak et al 1983). This may be an alternative mechanism for how GA ameliorates PLP-induced EAE. That is, GA induces MBP reactive Th2 cells to release the same protective cytokines which in turn downregulate the re- sponse of PLP-reactive Th1 cells. This has been called “bystander protection”. The therapeutic implications of this are evident (see below). In EAE, Th-1 cells are thought to be mainly responsible for the disease state, since the disease can be transmitted to naïve syngeneic recipients by transfer of Th-1 cells, and reso- lution of disease is associated with emergence of Th-2 cells. By analogy, Th-1 cells are thought to have a pathogenic role Neuropsychiatric Disease and Treatment 2007:3(2)