Mechanisms of Oral Tolerance

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Key points

  • The gut has adapted a unique set of immune cells and sites to respond to antigens appropriately.

  • Numerous characteristics of antigens are important for the induction of oral tolerance.

  • Use of the oral route to establish tolerance holds promise for food-based antigens as well as other disease states.

Role of the gut immune system

The gut-associated lymphoid tissue (GALT) is the largest immune system in the body.1 Approximately 30 kg of food proteins reach the human intestine during a year, and 130 to 190 g of these proteins are absorbed daily in the gut.2 The microbiota in the intestine is an additional major source of natural antigenic stimulation with a perhaps underappreciated number of bacteria colonizing the human intestinal mucosa (∼1012 microorganisms per gram of stool).3 The physiologic role of the GALT is the

Regulatory T cells

It is now recognized that there are multiple mechanisms of oral tolerance, and one of the prime determinants is the dose of antigen fed.4, 12, 13, 14, 15, 16, 17, 18, 19 Low doses favor the induction of regulatory T cell (Tregs), whereas higher doses favor the induction of anergy or deletion.20 These mechanisms are not exclusive, especially at higher doses. One of the major mechanisms of oral tolerance is the induction of Treg cells, a process that is related to the gut DCs and linked to both

Anergy

T-cell unresponsiveness or anergy is one of the primary mechanisms by which tolerance is maintained in self-reactive lymphocytes and anergy is induced in high-dose oral tolerance. The upregulation of anergy-associated genes is largely dependent on nuclear factor of activated T cells.31 Orally tolerized T cells can form conjugates with antigen-presenting cells, but they are defective in immunologic synapse formation.32 Similarly, T cells made anergic in vivo following oral antigen can inhibit

Lessons learned from oral anti-CD3

The investigation of oral tolerance has classically involved the administration of oral antigen followed by challenge with same/similar antigen (albeit usually in an adjuvant) to demonstrate antigen-specific tolerance. One interesting experimental system that has been used to study T-cell function in oral tolerance is the use of TCR transgenic mice, in which all T cells have a common TCR. Using such mice, Dr Weiner and colleagues36 investigated how oral administration of an antigen affected

Site of tolerance to oral antigens: gut versus systemic

One of the characteristic features of oral tolerance to soluble antigens is that it can involve the entire animal.16 This is difficult to explain, however, as current thought focuses on anatomic compartmentalization within the mucosal immune system. In other words, antigen uptake and recognition are believed to be restricted to the GALT, MLNs, DCs, and intestinal epithelial cells (discussed previously), therefore limiting the effects to the intestinal mucosa. A possible explanation, and one

Summary

Despite the extensive literature on the effectiveness of oral tolerance to treat diseases in animals, this approach has yet to successfully translate to clinical treatment of IgE-mediated food allergy or even food hypersensitivity. With the advent of technologies such as mass cytometry and single-cell gene expression profiling applied to food allergy, we can only expect to reach a better understanding of cellular processes regulating oral tolerance. In the coming years, it will likely be time

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    Disclosure: National Institutes of Health grant recipient (K08 AI085190); UpToDate author.

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