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To date, the majority of therapies approved by the US Food and Drug Administration (FDA) for autoimmune disease have focused on the global inhibition of immune inflammatory activity. Although nonspecific immune suppression is partially effective in inhibiting autoreactive immunecell function, the drugs used to suppress the immune response have numerous side effects and continuous therapy is not conducive to longterm host survival. The goal of ongoing research in immune tolerance is the development of autoantigenspecific treatments that allow for the specific blockade of the deleterious effects of selfreactive immunecell function, while maintaining the ability of the immune system to clear nonself antigens. Although CD4+ T cells can discriminate between specific peptide antigens, the Tcell receptor (TCR) cannot intrinsically distinguish self from nonself peptides. During thymic selection of CD4+
T cells, the majority of Tcell clones with highaffinity TCRs that recognize self are deleted as a consequence of selfantigen presentation by thymic epithelial cells1.
However, the thymic negativeselection process is not perfect, and therefore selfreactive CD4+ T cells are present in the peripheral Tcell repertoire of healthy individuals. For example, myelin basic protein (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4155&ordinalpos=2&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSum
Web End =MBP )specific CD4+ T cells can be found in the peripheral blood of both healthy individuals and individuals with http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=126200
Web End =multiple sclerosis (MS)2. The difference between the MBPspecific CD4+ T cells in these two groups is
the activation status of the cells. Selfreactive CD4+
T cells that escape negative selection in the thymus must be held in check by additional peripheral tolerance mechanisms, and it is thought that the ability to tightly control and avoid the activation of peripheral selfreactive T cells is crucial for avoiding autoimmunity.
The advantage of peptidespecific therapy over other forms of therapy is that it lacks potential metabolic activity and can limit the range of the response to the desired pathogenic peptide epitopes without increasing the possibility for hyperactivation of selfreactive T cells. Likewise, the use of different routes of administration (such as the intravenous administration of antigencoupled cells or the mucosal or intravenous administration of soluble peptides), the dose schedule and the adjuvants used in combination with the therapy may provide a more efficient means to specifically induce tolerance and/or induce the deviation of the response towards an antiinflammatory cytokine profile....