Immunomodulation of experimental autoimmune diseases via oral tolerance

The concept of oral tolerance refers to a form of peripheral tolerance in w hich mature lymphocytes in the peripheral lymphoid tissues are rendered non functional or hyporesponsive by prior oral administration of an antigen. Th e primary mechanisms mediating oral tolerance include deletion, anergy of a ntigen-specific T cells and active cellular suppression, the primary determ ining factor being the dose of fed antigen. Low doses favor active suppress ion, whereas high doses favor deletion and anergy. Active cellular suppress ion is mediated by the induction of regulatory T cells in the gut-associate d lymphoid tissue, which migrate to the systemic immune system. One of the primary mechanisms of active cellular suppression is via secretion of suppr essive cytokines such as TGF-beta, IL-4, and IL-10 following antigen-specif ic triggering. TGF-beta is produced both by CD4(+) and CD8(+) GALT-derived T cells and is an important mediator of the active suppression component of oral tolerance. CD4(+) cells that primarily produce TGF-beta appear to be a unique T-cell subset and termed Th3 cells. Oral tolerance was successfull y studied in a variety of experimental models far autoimmune diseases, amon g them experimental autoimmune encephalomyelitis, experimental arthritis, e xperimental anti-phospholipid syndrome, experimental autoimmune uveoretinit is, experimental insulin dependent diabetes mellitus (IDDM), and experiment al autoimmune myasthenia gravis. The results obtained in experimental anima l models have led to the conduction of several clinical trials of oral tole rance in patients with multiple sclerosis, rheumatoid arthritis, uveitis, a nd IDDM. Conflicting results were obtained, and although some improvement h as been noted in some of the patients, broad ranging clinical improvement h as not yet been observed. A more accurate choice of antigens, as well as mo re precise dosing and timing of antigen-administration might lead to better results in the future.