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types of cells, including CD4 minus and CD8 minus positive suppressor cells have been shown to suppress EAE in some animal models, but the role of suppressor T cells and their potential for therapeutic use in MS are far from clear. CD25+ T cells are closest to the classic suppressor cells, but they are enigmatic and not well characterized in terms of antigen specificity, function, and mechanism of action. Their existence has been postulated on the basis of transfer and depletion studies in vivo (Don Mason, Ethan Shevach), as in the NOD mouse model of insulin-dependent diabetes mellitus (IDDM), in neonatal thymectomy models of multiorgan infiltration (Sakaguchi), and also in T-cell receptor transgenic, “monoclonal” mice (Tonegawa; Lafaille). Evidence for a role of these cells in CNS-specific autoimmune diseases is indirect at best.

Immunodeviation

Approach potential involves inducing immunodeviation of myelin-specific T cells, that is, shifting the balance of production from Th1 to Th2 cells. This is a crowded field in MS research, as in other putative autoimmune diseases. Several private firms are investigating this strategy, and the committee feels this approach is already receiving adequate attention and is not lacking for encouragement. Further, in the pathogenesis of EAE and MS, there is no clear distinction between “good” Th2 and “bad” Th1 T cells. Both cell types might produce pathogenic inflammation in different situations.

Genetic Engineering

Another possible innovative therapy would be to use genetically engineered autoimmune T cells. Even though the precise pathological roles of T cells and their autoantigens are unresolved, this line of research has generated many approved or emerging therapies. These include vaccination strategies, which use either attenuated myelin-specific T cells97,33 or peptides representing myelin-specific T-cell receptors3 as vaccines to strengthen the body's own regulatory responses against pathogenic T cells (reviewed in 1998 by Zhang et al.).120 Also under development are “altered peptide” therapies that use peptide analogues of myelin protein segments to induce autoreactive T cells to produce protective, rather than pathogenic, cytokine mediators.96

Neuroprotection

Recent studies have elegantly demonstrated the loss of axons in chronic MS lesions. As discussed elsewhere in this report, the precise mechanisms leading to axonal degeneration in MS are at present unknown. Axons can degenerate as a result of the loss of trophic support of their myelin sheaths. Alternatively, they



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