Oral tolerance is a therapy that coaxes immune system cells to tolerate rather than attack the specific proteins targeted in autoimmune diseases.
Oral tolerance therapy, which was first introduced in the 1940s, is a promising therapy for diabetes, uveitis and other autoimmune disorders. In recent years, oral tolerance therapy has been used successfully in animal models of experimental autoimmune encephalitis (a disorder similar to multiple sclerosis), uveitis, thyroiditis, myasthenia, arthritis and diabetes and for non-autoimmune inflammatory conditions including asthma, atherosclerosis, allergy, colitis, stroke and animal models of Alzheimer's disease. In humans, oral tolerance has been tested in autoimmune conditions of multiple sclerosis (MS), rheumatoid arthritis, uveitis, inflammatory bowel disease, diabetes, and in allergy, contact sensitivity to dinitrochlorbenzene and nickel allergy. Currently, trials for oral tolerance therapy are being conducted for a number of different autoimmune disorders.
WHAT IS ORAL TOLERANCE THERAPY?
Oral tolerance therapy is a physiologic mechanism that involves the administration of proteins resembling proteins targeted in autoimmune diseases. Over time, the immune system cells of the gastric mucosa recognize and tolerate these administered proteins. This tolerance prevents the immune system from reacting with the body's natural proteins.
USES IN AUTOIMMUNE DISEASE
In the original studies of oral tolerance, simple proteins such as chicken meat were used. Today, synthetic proteins are being studied. Oral tolerance therapy is an attractive therapy for autoimmune and inflammatory disorders because of its lack of toxicity, ease of administration over time, and antigen-specific mechanism of action. Its success depends on finding optimal doses, developing immune markers to assess its effects, finding the optimal route, for instance oral vs. nasal administration of a particular protein, formulation, and combination therapies.
Oral tolerance has shown particularly good results in trials of oral insulin used to prevent diabetes in at-risk populations. Positive results have also been observed in phase II clinical trials although no effect was seen in phase III trials of glatiramer acetate (GA) in MS. New trials using GA for MS are currently underway.
Oral tolerance induction with peptide B27PD had an ameliorating effect in patients with uveitis, which was also observed in the five-year follow up period. However, trials with pyruvate dehydrogenase for patients with primary biliary chirrhosis showed no reduction in liver function tests and no immunological improvement after 12 months.
Although animal trials using thyroglobulin protein for thyroiditis in mice were successful, the amounts needed for humans and the fact that thyroiditis is a treatable disease suggest that trials in humans are a long ways off. The use of oral tolerance for patients with Graves' ophthalmopathy (thyroid eye disease) is more likely to occur first.
Resources:
Faria AM, Weiner HL, Oral Tolerance, Immunol Rev, 2005 Aug;206:232-259.
American Diabetes Association http://www.diabetes.org
Autoimmune Incorporated, http://www.autoimmuneinc.com
Vida Foubister and Beth Schachter, A Gut Response to Foreign Invaders, The New York Academy of Sciences, Apr 25, 2004.
