Oral tolerance in the treatment of inflammatory autoimmune diseases

Abstract

Oral tolerance refers to the oral administration of protein antigens, which induces a state of systemic nonresponsiveness specific for the fed antigen. This method of inducing immune non-responsiveness has been applied to the prevention and treatment of experimental animal models of autoimmune disease. Extensive research in this area over the past ten years has led to the conclusion that two mechanisms are operative in the mediation of oral tolerance--active suppression and clonal anergy/deletion. A number of factors have been identified that determine which mechanism of tolerance is operative--antigen dose, antigen form, and the timing of antigen administration. Work from these animal models has recently been extended into human clinical trials of multiple sclerosis, rheumatoid arthritis, diabetes, uveitis, and allergy, with differing degrees of success. In this review, a discussion is provided of the animal model systems where oral tolerance has been applied and the clinical trials where an oral tolerization approach has been attempted. Moreover, recent mechanistic studies are reviewed and a model proposed for the induction of oral tolerance.

Helper (CD4+) and Cytotoxic (CD8+) T Cells Promote the Pathology of Dystrophin-Deficient Muscle

“…For example, characterization and isolation of muscle reactive T cells might allow for the identification of the antigenic protein. This knowledge might then be used to induce specific tolerance through ingestion, as tested in ongoing clinical trials to treat MS, rheumatoid arthritis, and insulin-dependent diabetes mellitus (24). Less specific approaches to immune intervention would include the potential use of antibodies against the T cell receptor (TCR) to prevent recognition of antigen; this could be especially promising if muscle-reactive T cells expressed a particular TCR, such as V␤2 in DMD (13).…”

Peyer's patches are required for oral tolerance to proteins

“…In earlier studies, this type of immunological response was dubbed ''oral tolerance'' and the concept was used to refer specifically to a failure to induce systemic immune responses after oral delivery of protein (3). It is now generally agreed that oral tolerance is established and maintained at the level of T cells (4)(5)(6)(7)(8)(9)(10)(11). Two distinct forms of T-cell unresponsiveness have been proposed as major mechanisms for the induction of oral tolerance.…”

Macrophage Biology and Pathobiology in the Evolution of Immune Responses: A Functional Analysis

“…The above considerations do not negate the essential role of 'suppressor' T cells in alleviating, or preventing, autoimmune disease following various regimes of oral (or nasal) presentation of auto-antigen [181,182]. However, a common thread running through all oral tolerance induction protocols is that they can only be effective if the site of antigen uptake provides an anti-inflammatory innate cytokine micro-environment, and the mode of antigen presentation does not evoke an innate inflammatory response.…”