Journal of Pediatric Gastroenterology & Nutrition:
The Use of Oral Tolerance in the Therapy of Chronic Inflammatory/Autoimmune Diseases
Mayer, Lloyd; Shao, Ling
Department of Medicine and Immunobiology, Mount Sinai Medical Center, New York, New York.
Address correspondence and reprint requests to: Dr. L. Mayer, Department of Medicine and Immunobiology, Mount Sinai Medical Center, 1425 Madison Ave, New York, NY 10029 (e-mail firstname.lastname@example.org).
The unique nature of the mucosal immune response may be the consequence of an enormous antigenic burden of dietary antigens and commensal bacteria that are in constant contact with the intestinal epithelium. Immune responses to these beneficial and/or harmless antigens must be prevented to maintain the integrity of the gut and allow for nutrient absorption. Defects in this regulated state, such as immune responses to normal commensal flora, are thought to be an important contributing factor in the development of Crohn’s Disease, an inflammatory disorder of the gastrointestinal tract.
One of the hallmarks of this regulated state is the phenomenon of oral tolerance. Oral tolerance was first observed by physicians in the 19th century but not studied rigorously until the early 1900s by several investigators studying mechanisms of allergy and anaphylaxis. Investigators noted that the response to an antigen was dependent upon the route of administration. In particular, it was well established that repeated subcutaneous inoculation or repeated cutaneous application of a hapten could lead to sensitization of type I (anaphylaxis) and type IV (delayed-type) hypersensitivity reactions, while intravenous introduction of that same antigen led to a diminished immune response. In 1946, Merill Chase demonstrated that oral administration of a contact-sensitizing agent (2,4-dinitrochlorobenzene) did not lead to sensitization but, rather, prevented the animal from eliciting an immune response to subsequent intracutaneous injections and cutaneous challenges.
Oral Tolerance: Active Non-Response to an Antigen Administered Via the Oral Route
Although oral tolerance was first described in 1911 (1), it was not until the later 1970s that investigators started to address the mechanisms involved (2–4). An expansion of interest has evolved in the past 20 years as various laboratories have attempted to use this form of induced immunosuppression to counteract various chronic inflammatory/autoimmune diseases. A clearer understanding of the parameters regulating oral tolerance has emerged. First and foremost is the observation that multiple forms of tolerance exist. Initial studies by Challacombe et al. (2), Mowat et al. (3), and Waksman et al (4) all documented that regulatory CD8+ T cells existed in the spleen following oral antigen administration and that these cells, but not CD4+ T cells, could transfer the tolerant state to a naive animal. The mechanism whereby these CD8+ T cells were activated was not elucidated. Richman et al. (5) and Santos et al. (6) subsequently demonstrated that tolerance could also be transferred with Peyer’s patch CD4+ T cells as well. Friedman et al. (7) introduced the concept of low and high dose oral tolerance (analogous to systemic tolerance) where low dose feeding regimenns induced the activation of regulatory cells whereas higher doses resulted in deletion or induction of anergy in antigen reactive cells (8). In low dose oral tolerance, antigen reactive CD4+ T cells were shown to secrete regulatory cytokines such as TGFβ, IL10 and IL4. These regulatory “Th3” cells not only suppress Ag specific responses but also mediate what has been termed bystander suppression (7). The inductive phase is antigen specific; the effector phase, once activated, is not.
Oral tolerance has been used to prevent and/or treat mice with a variety of induced autoimmune disorders. Its efficacy has been quite dramatic in most of these T-cell mediated disorders (experimental allergic encephalomyelitis, collagen induced arthritis, uveitis, not expandable mouse, autoimmune thyroiditis, autoimmune myasthenia gravis) (8–13). In fact, in an animal model of Th1-mediated colitis, the trinitrobenzene sulfonic acid model reported by Strober et al., feeding colonic extracts that have been haptenated with trinitrobenzene sulfonic acid prevented the development of mucosal inflammation (13). This group proposed that similar approaches may be useful for patients with inflammatory bowel disease (IBD). Three problems exist with this thinking. First, the two published trials (and unpublished work) assessing the ability of oral tolerance to ameliorate chronic inflammation (multiple sclerosis and rheumatoid arthritis) were less than impressive (14,15). The situation is quite different in genetically outbred humans in terms of their ability to be orally tolerized to autoantigens. Second, as an extension of this latter statement—that oral tolerance in humans may be quite different than that seen in mouse and rat—the published studies looking at oral tolerance in humans have shown modest inhibition of T-cell responses and no effect on antibody responses (16). Lastly, in a study performed in our laboratory, we demonstrated that patients with inactive IBD (both ulceritive colitis and Crohn’s disease) not only failed to tolerize with low doses of keyhole limpet hemocyanin given orally but were actually primed for an immune response against this antigen. This observation, linked with our previous report on the lack of suppressor cell generation in IBD mucosa, suggests that an approach at oral tolerization to colonic auto-antigens may not be effective.
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2. Challacombe SJ, Tomasi TB. Systemic tolerance and secretory immunity after oral immunization. J Exp Med
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10. Nussenblat RB, Caspi RR, Mahdi R, et al. Inhibition of S-antigen induced experimental autoimmune uveoretinitis by oral induction of tolerance with S-antigen. J Immunol
11. Zhang JA, Davidson L, Eisenbarth G, Weiner HL. Suppression of diabetes in NOD mice by oral administration of porcine insulin. Proc Natl Acad Sci
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14. Weiner HL, Mackin GA, Matsui M, et al. Double-blind pilot trial of oral tolerization with myelin antigens in multiple sclerosis. Science
15. Trentham DE, Dynesius-Trentham RA, Orav EJ, et al. Effects of oral administration of type II collagen on rheumatoid arthritis. Science
16. Husby S, Mestecky J, Moldoveanu Z, Holland S, Elson CO. Oral tolerance in humans. T cell but not B cell tolerance after antigen feeding. J Immunol
© 2004 Lippincott Williams & Wilkins, Inc.
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