Immunology Today, voL 8, No. 3, 1987

The regulation of immune responses _to dietary protein antigens Hypersensitivity reactions to food proteins are rare, probably because the intestinal immune system has evolved efficient means of preventing such responses. In this article Allan Mowat reviews the mechanisms underlying the induction of immunological tolerance after feeding proteins and suggests how a breakdown in oral tolerance may lead to potentially harmful hypersensitivity in the intestine.

AllanMd. Mowat

The food antigens of greatest immunological relevance are soluble proteins. The most extensively studied experimental model of oral tolerance to proteins is ovalbumin (OVA) administration in mice, in which systemic immune responses can be suppressed by up to 90-100% after a single feed of OVA (Fig. 1). Systemic tolerance is the usual consequence of feeding a wide The intestinal immune apparatus has to mount rapid and range of doses o÷ OVA and it may persist for up to two potent effector response~ to prevent invasion by years after one feed, yet very low doses may prime rather pathogenic viruses, bacteria and other parasites. Yet than tolerize the animal (Fig. 1). despite the numerous potential antigens in a normal Systemic unresponsiveness occurs after feeding a wide diet, hypersensitivity reactions to dietary constituents are range of other thymus-dependent antigens, including uncommon. The intestinal immune system seems, therecontact sensitizing agents7-~°, heterologous red fore, to have evolved means of preventing hypersensitivcells 11-16 and inactivated bacteria or viruses17.~8. ity to orally administered antigens. This article will review Thymus-independent antigens, however, usually prime some of the mechanisms which regulate immune rethe animal for an active immune response, even when sponses to dietary proteins and indicate how a breakpresented in association with a T-dependent down in this homeostatic system may lead to disease. antigen 17.~9. It is also generally more difficult to induce oral tolerance to particulate antigen than soluble Immune responsesto fed protein antigens antigen 3, while oral administration of live allogeneic Small amounts of orally administered proteins escape cells or virusls.2° generates local and systemic immunity. enzymatic digestion in the intestine and are absorbed as These findings may provide an experimental basis for the intact antigens ~. Up to 2% of fed protein may be apparent ability of the intestinal immune system to absorbed in this way and there are three major immunoprevent hypersensitivity to soluble, non-replicating antilogical consequences. A local secretory IgA antibody gens while mounting active immunity to particulate, response may develop in the intestine; more rarely, the thymus-independent antigens of the kind presented by animal may show evidence of a systemic immune repotentially invasive organisms. sponse; or, most frequently, a state of immunological Oral tolerance affects all aspects of the systemic tolerance may develop. Although there is some evidence immune response which have been studied. A single from animal studies that production of local IgA may feed of a protein antigen suppresses systemic IgM, IgG inhibit intestinal uptake of immunogenic protein 2.3, and IgE antibody responsesz.3,19.z~-z4, as well as the there is no direct evidence that this prevents hypersensicell-mediated immune (CMI) responses measured by tivity in vivo. Therefore, in this review, I shall concentrate lymphocyte proliferation in vitro or delayed-type on the possible importance of tolerance to dietary hypersensitivity (DTH) in vivo 3.~9.z4,2s. Furthermore, proteins in the prevention of food hypersensitivity. although earlier studies suggested that feeding proteins produced concomitant suppression of systemic IgG and Induction of tolerance by feeding antigens DTH responses but induced local production of specific 'Oral tolerance' is the state of specific immunological IgA antibody, recent evidence suggests that IgA producunresponsiveness induced by prior oral administration tion may also be toterized in protein-fed animai~26.27. of antigen. It has been described in most laboratory Similarly, the development of (presumably) IgAanimals. dependent exclusion of fed antigens in different strains The possibility that oral ingestion of antigen might of mice does not correlate with the level of systemic modify subsequent systemic immune responses was first tolerance 28. These observations are evidence against a raised by the anecdotal report of Dakin (1829) who critical role for local IgA in preventing hypersensitivity to described how South American Indians ate poison ivy food proteins. leaves in an attempt to prevent contact sensitivity reacIgE and DTH responses are the mechanisms most tions to the plant4. Subsequently, Wells and Osborne readily tolerized by feeding proteins and the resulting showed that feeding proteins to guinea pigs could inhibit tolerance is also more stable 21.24.27'29-31. As these resystemic anaphylaxis to the same material s, while the sponses are the form of immunity most frequently experiments of Chase using contact sensitizing agents associated with clinical food hypersensitivity, prevention established the immunological basis of what became of food-specific IgE and DTH may be the major known as the Sulzberger-Chase phenomenon6. Over the homeostatic role of oral tolerance. last ten years, oral tolerance has been subject of increasingly intensive study. Mechanismsof oral tolerance As with parenterally induced immunological tolerance, oral tolerance is a highly complex phenomenon which Department of Bacteriology and Immunology, Westem Infirmary, may involve a wide range of immunoregulatory mechanGlasgowG11 6NT,UK (~'~1987, ElsevierPubhcatlons,Cambridge 0167 4919/87/$02 00

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The regulation of immune responses to dietary protein antigens.

Hypersensitivity reactions to food proteins are rare, probably because the intestinal immune system has evolved efficient means of preventing such res...
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