ORAL TOLERANCE - IMMUNOLOGICAL MECHANISMS AND TREATMENT OF ANIMAL ANDHUMAN ORGAN-SPECIFIC AUTOIMMUNE-DISEASES BY ORAL-ADMINISTRATION OF AUTOANTIGENS

Oral tolerance is a long recognized method to induce peripheral immune tolerance. The primary mechanisms by which orally administered antige n induces tolerance are via the generation of active suppression or cl onal anergy. Low doses of orally administered antigen favor active sup pression whereas higher doses favor clonal anergy. The regulatory cell s that mediate active suppression act via the secretion of suppressive cytokines such as TGF beta and IL-4 after being triggered by the oral tolerogen. Furthermore, antigen that stimulates the gut-associated ly mphoid tissue preferentially generates a Th2 type response. Because th e regulatory cells generated following oral tolerization are triggered in an antigen-specific fashion but suppress in an antigen nonspecific fashion, they mediate ''bystander suppression'' when they encounter t he fed autoantigen at the target organ. Thus it may not be necessary t o identify the target autoantigen to suppress an organ-specific autoim mune disease via oral tolerance; it is necessary only to administer or ally a protein capable of inducing regulatory cells that secrete suppr essive cytokines. Orally administered autoantigens suppress several ex perimental autoimmune models in a disease- and antigen-specific fashio n; the diseases include experimental autoimmune encephalomyelitis (EAE ), uveitis, and myasthenia, collagen- and adjuvant-induced arthritis, and diabetes in the NOD mouse. In addition, orally administered alloan tigen suppresses alloreactivity and prolongs graft survival. Initial c linical trials of oral tolerance in multiple sclerosis, rheumatoid art hritis, and uveitis have demonstrated positive clinical effects with n o apparent toxicity and decreases in T cell autoreactivity.