The concept of oral tolerance refers to a form of peripheral tolerance in which mature lymphocytes in the peripheral lymphoid tissues are rendered nonfunctional or hyporesponsive by prior
oral administration of an
antigen. The primary mechanisms mediating oral tolerance include deletion, anergy of
antigen-specific T cells and active cellular suppression, the primary determining factor being the dose of fed
antigen. Low doses favor active suppression, whereas high doses favor deletion and anergy. Active cellular suppression is mediated by the induction of regulatory T cells in the gut-associated lymphoid tissue, which migrate to the systemic immune system. One of the primary mechanisms of active cellular suppression is via secretion of suppressive
cytokines such as
TGF-beta,
IL-4, and
IL-10 following
antigen-specific 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 successfully studied in a variety of experimental models for
autoimmune diseases, among them
experimental autoimmune encephalomyelitis,
experimental arthritis, experimental
anti-phospholipid syndrome, experimental autoimmune uveoretinitis, experimental
insulin dependent diabetes mellitus (
IDDM), and
experimental autoimmune myasthenia gravis. The results obtained in experimental animal models have led to the conduction of several clinical trials of oral tolerance in patients with
multiple sclerosis,
rheumatoid arthritis,
uveitis, and
IDDM. Conflicting results were obtained, and although some improvement has been noted in some of the patients, broad ranging clinical improvement has not yet been observed. A more accurate choice of
antigens, as well as more precise dosing and timing of
antigen-administration might lead to better results in the future.