Oral tolerance is a long-recognized mechanism of inducing antigen-specific peripheral immune tolerance. In the past decade a large number of investigators have successfully applied oral tolerance to the treatment of autoimmune diseases in animal models by feeding autoantigens, and human trials have begun with this approach as well (1). In this issue of the Proceedings, Teitelbaum et al.(2) report that oral tolerance using Copolymer 1 (Cop 1, Copaxone, glatiramer acetate), which simulates myelin basic protein (MBP) immunologically, is effective in both the rat and mouse models of experimental allergic encephalomyelitis (EAE) and indeed may be more effective than MBP itself. Injectible Cop 1 has been used successfully to treat both EAE (3) and the human disease multiple sclerosis (MS)(4). These results raise the possibility that orally administered Cop 1 may be an effective treatment for MS.

Although the phenomenon of oral tolerance has been known since the turn of the century, it is only recently that the mechanisms underlying oral tolerance have been elucidated (5). Orally administered proteins and oral peptides are active immunologically and have clear immunologic effects on the gut-associated lymphoid tissue (6), which constitutes approximately 70% of the immune reactive cells in the body. There are multiple mechanisms by which orally administered antigen induces tolerance, the primary determining factor being the dose of antigen administered (7). Low doses of antigen induce regulatory T cells that act by secreting anti-inflammatory cytokines such as transforming growth factor (TGF) type, IL-10, and IL-4 (8, 9). Higher doses induce anergy or deletion of cells specific for the fed antigen (10, 11). These multiple mechanisms most probably evolved to maintain tolerance to the large variety of proteins that are ingested over a wide dose range.