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  • Review Article
  • Published:

Therapeutic potential of oral tolerance

Nature Reviews Immunology volume 4, pages 407–419 (2004)Cite this article

Key Points

  • The immune response to an antigen depends on the route by which antigen enters the body. When antigen is introduced orally, under normal circumstances, the immune response to that antigen is one of tolerance.

  • Oral tolerance occurs by two distinct mechanisms based on the dose of antigen given. High doses of antigen lead to anergy or deletion of antigen-specific cells, whereas low doses of antigen generate regulatory cells.

  • Oral tolerance can potentially be used to treat several autoimmune and inflammatory diseases, as well as to prevent tissue-graft rejection.

  • Many factors influence the induction of oral tolerance. Important factors include the dose of antigen, the antigen itself, the age at which tolerance is induced, gender and background genetics.

  • Animal models have shown that feeding antigen prior to disease onset is an effective method to prevent disease. By contrast, feeding antigen after the onset of disease might require the addition of adjuvants to ameliorate disease.

  • Human disease is more complex than animal models, so lessons learned from animal models must be validated in humans.

Abstract

The immune system has the daunting task of distinguishing between self and non-self. The mucosal immune system, present along the respiratory, gastrointestinal and genitourinary tracts, has the additional burden of coexisting with an abundance of dietary antigens and lumenal bacterial flora. A key feature of the mucosal immune system is its ability to remain tolerant to these antigens while retaining the capacity to repel pathogens effectively. Furthermore, tolerance generated at mucosal surfaces can translate to a more generalized systemic tolerance — a characteristic of great therapeutic potential, but with many unforeseen complexities that are explored in this review.

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Figure 1: Induction of oral tolerance.
Figure 2: The path to oral tolerance.
Figure 3: Potential mechanisms of oral tolerance.

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Acknowledgements

This work is supported by the National Institutes of Health.

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    Lloyd Mayer & Ling Shao

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Glossary

CONTACT-SENSITIZING AGENT

A substance that results in a local inflammatory response to that substance following repeated cutaneous or subcutaneous exposure.

ORAL TOLERANCE

Active non-response to an antigen administered through the oral route.

COMMENSAL BACTERIA

Any one of the harmless or beneficial bacteria that colonize the small and large intestine.

NON-PROFESSIONAL ANTIGEN-PRESENTING CELLS

Cells that can be induced to express antigen-presenting molecules or non-classical antigen-presenting molecules. These cells also often lack expression of co-stimulatory molecules such as CD80 and CD86.

NK1.1+ T CELLS

Recently, these cells have been shown to be restricted by the non-classical MHC class Ib molecule CD1d. These cells respond to the antigens α-galactosylceramide and glycerol-phosphatidylinositol in mice and have important functions in immunity against infections and malignancies.

PEYER'S PATCHES

Organized lymphoid structures in the small intestine, underlying M cells. Peyer's patches consist of a T-cell zone surrounding a B-cell zone, similar to germinal centres in lymph nodes.

MICROFOLD CELLS

(M cells). Specialized epithelial cells that have a characteristic shape with a deep basolateral pocket and little cytoplasm. This makes them efficient at transporting insoluble materials across the epithelial-cell barrier, where these antigens immediately encounter macrophages and dendritic cells.

FMS-LIKE TYROSINE KINASE 3 LIGAND

(FLT3L). A cytokine that promotes the clonal expansion of dendritic cells in vivo.

PERIPHERAL TOLERANCE

Potentially autoreactive T cells that have escaped negative selection in the thymus (central tolerance) can be deleted or anergized by one of several mechanisms. Deletion can be mediated by high-affinity T-cell receptor (TCR) crosslinking or by CD95–CD95L-mediated apoptosis. Anergy can occur when incomplete activation signals are sent through the TCR (low-affinity interactions) or when there is a lack of co-stimulation during activation.

ANERGY

A reversible immune hyporesponsiveness to antigen. Incomplete activation signals mediated by low-affinity T-cell receptor interactions or a lack of co-stimulation can lead to anergy. Anergy has been shown to be reversible by stimulation with antigen and interleukin-2.

BYSTANDER SUPPRESSION

Antigen non-specific inhibition of the immune response by virtue of temporal and physical proximity to regulatory cells.

SYSTEMIC ADJUVANTS

Substances that help initiate a robust immune response. Typically, adjuvants contain a mixture of substances that mimic an active infection, such as bacterial cell-wall components to simulate danger signals and emulsifiers to allow for the slow release of antigen.

MIMETOPE

An epitope that structurally resembles another. Epitopes are three-dimensional structural motifs recognized by antibodies or by T-cell receptors (in the context of MHC). Similar or identical three-dimensional structures can be created by different peptides or synthetic compounds and can mimic the activity of the original antigen.

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Mayer, L., Shao, L. Therapeutic potential of oral tolerance. Nat Rev Immunol 4, 407–419 (2004). https://doi.org/10.1038/nri1370

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