rizvi et al Immunology of MS Cur rent hypotheses support the idea that MS is an immunologically mediated disease. Although the etiology is unknown, it is likely that exposure to a variety of antigens, including viruses and toxins, results in activation of T cells. These T cells (T helper 1) recognize antigens presented by antigen-presenting cells and subsequently release pro- inflammatory cytokines, such as tumor necrosis factor (TNF), inferferon-γ, and IL-12, and then subsequently invade the central nervous system (CNS). In the CNS, T cells are further activated by antigens found on antigen-presenting cells, which leads to further secretion of pro-inflammatory cytokines and chemokines. A variety of proposed mechanisms may then lead to demyelination and axonal transaction (Martin et al 2001) (Table 1). Table 1 Possible mediators of neuronal demyelination and degeneration in MS T-cell mediated Antibodies Cytokines Complement Nitric oxide Others (viruses, bacteria, free radicals) History of GA and mechanism of action An important step in understanding the immune mechanisms in MS was the development of an animal model of demyelina- tion. Experimental allergic encephalomyelitis (EAE), a T cell-mediated disease, can be induced in susceptible animals by inoculating them with CNS tissue such as myelin basic protein (MBP) (Bernard et al 1992). Copolymers (copolymer 1 up to copolymer 11) were synthesized with amino acid composition similar to MBP. None of them were able to induce EAE but several were able to prevent or minimize EAE in animals inoculated with MBP. Copolymer 1 (L- glutamate, L-tyrosine, L-alanine, and L-lysine) appeared to be the most potent and showed a consistent effect in several animal models, including primates (Teitelbaum et al 1971). It was also shown to be safe. effect of GA on T cells GA is a synthetic molecule composed of four amino acids (L-alanine, L-glutamic acid, L-lysine, and L-tyrosine). These are the same amino acids represented in MBP. GA was originally designed as a synthetic model of MBP for the purpose of inducing EAE, an experimental animal model of MS. However, in vitro studies proceeded to show the opposite 284 effect, as GA appeared to prevent the induction of EAE. Evidence suggests that the structural similarity between GA and MBP may be partly responsible by way of competi- tive mechanisms and/or cross-reactivity for the therapeutic benefit of GA. EAE studies suggest that GA may compete with MBP for antigenic binding to the MHC II complex on antigen-presenting cells in the CNS. This mechanism alone is unlikely to function in vivo because GA is rapidly degraded after subcutaneous administration before it can enter the CNS (Lobel et al 1996). However, this competition may function in vivo if it occurs in the periphery or at subcutaneous SC injection site where GA may confront MBP-specific T cells before GA is degraded. The resulting GA/MHC complex may then bind preferentially to MBP-specific T cells over MBP/MHC complexes and induce alterations to the T cells. One such alteration may be a phenotypic shift in the T cells from Th1 to Th2 cells, thus increasing anti-inflammatory mechanisms (Duda et al 2000; Chen et al 2001; Neuhaus et al 2001). After activation in the periphery by daily immunization, GA has been demonstrated to selectively promote trans endothelial migration of Th2 cells across the blood–brain barrier (BBB) (Prat et al 2005). It is postulated that when the GA-specific Th2 cells are reactivated in the CNS by the presentation of degraded myelin components, they are stimulated to release anti-inflammatory cytokines such as IL-4, IL-6, and IL-10 (Neuhaus et al 2001). The release of anti-inflammatory cytokines then nonspecifically decreases the pathological inflammation in MS (Miller et al 1998; Brenner et al 2001; Dhib-Jalbut 2002; Yong 2002) (Figure 1). GA and neuroprotection The burden of disease in MS appears to be propagated by more than just inflammation and secondary demyelination from acute relapses. An important mechanism in MS appears to be a parallel ongoing process of neuro-degeneration. Data pointing towards neurodegeneration as a significant component of the immunopathology of the initial phases of MS are increasing (Trapp et al 1998). The mechanism of this neuronal degeneration is unknown and represents an important area of interest and a potential target for future therapeutics (Neuhaus et al 2003). Much of the interest in potential mechanisms of neuroprotection surround the role of neurotrophic factors, particularly brain-derived neurotrophic factor (BDNF). BDNF is up-regulated in response to neuronal damage and may have a protective role against neuro-degeneration. BDNF is hypothesized to influence the neuronal response to trauma or degeneration via inhibition of cell death and international Journal of Nanomedicine 2006:1(3)