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vaccines. So far, even in model systems, the best results have been obtained by treatments close to the beginning of the appearance of symptoms.

Oral and nasal tolerance induction are very effective in regulating autoimmune diseases in animal models, and show some promise in human trials. Administration of antigen by these routes leads to a combination of effects, including deletional and anergic consequences as well as immune deviation. A deviated response that is often curative in animal models of diabetes and multiple sclerosis, for example, involves a switch from a Thl to a Th2 direction, and will be discussed below. Much of the benefit from the tolerance induced through the mucosal route may occur by deviation. It can be hoped that for clinical purposes, when the inciting antigen(s) is (are) known, tolerance induction may lead to a broadened effect via bystander suppression or regulatory spreading.

Immune Deviation

It is evident from model systems that the induction of a Th2 (anti-inflammatory) or a Th3 (regulatory cytokine) state of differentiation can prevent or down-regulate an autoimmune disease course. One of the favored ways of accomplishing this is through mucosal introduction of antigen, which generally deviates responses in a Th2 or Th3 direction. In the type I diabetes of the non-obese diabetic (NOD) mouse, treatment involving deviation has been shown to prevent the disease at a time well after its initiation, in the midst of increasing insulitis. This occurs in what is conceived to be a Thl mouse strain, particularly disposed towards inflammatory induction; in other strains of mice of the Th2 type, such as the BALB/c, certain autoimmune diseases are difficult to induce. The nature of the peptide chosen for therapy is an important ingredient: for example, determinants with high affinity for the MHC tend to induce Thl responses. On the other hand, altered peptide ligands may be designed so as to induce a Th2 or regulatory response. In allergic individuals, the reverse deviation, from Th2 to Thl, may be an effective route to therapy.

Receptor-Centered Regulation

The intrinsic regulatory properties of T- and B-cell circuits can be employed in vaccines. Accordingly, it has been shown in lupus that T cells that modulate B-cell activation can be induced with peptides derived from the B-cell receptor. Likewise, in such diseases as multiple sclerosis and its animal equivalent, experimental autoimmune encephalomyelitis (EAE), or collagen arthritis, regulatory T cells specific for antigenic determinants on the aggressive T-cells receptor have been shown to exert a curative effect. In the B10.PL mouse strain, which demonstrates a single spike transient EAE, such TcR-specific regulatory T cells can be demonstrated when disease disappears, and not earlier. Recently it



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