Could specific oral tolerance be a therapy for autoimmune disease?

doi:10.1016/0167-5699(90)90158-6

Immunology Today

Volume 11, 1990, Pages 396-399

https://doi.org/10.1016/0167-5699(90)90158-6 Get rights and content

Abstract

Several experimental autoimmune diseases have been successfully suppressed by the induction of specific oral tolerance. Here, Stephen Thompson and Norman Staines review the nature and mechanisms of this form of tolerance and discuss its possible applications in the control of human autoimmune diseases.

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Cited by (33)

Oral tolerance physiologic basis and clinical applications
2005, Mucosal Immunology, Two-Volume Set
Oral tolerance: Mechanisms and therapeutic applications
1999, Advances in Immunology
This chapter discusses the mechanisms and therapeutic applications of oral tolerance. The most striking characteristic of the gut mucosa is the abundance of the lymphoid tissue associated with it. There are 10¹² lymphoid cells per meter of human small intestine. Cell surface molecules and cytokines associated with inductive events in the gut that generate and modulate oral tolerance are not completely understood. Three major immunological consequences of oral antigen administration are described in the chapter—namely, (1) a local (noninflammatory) immune response resulting in the production of secretory immunoglobulin A (IgA), (2) a systemic inflammatory response with the generation of serum-specific antibodies, and (3) a systemic state of hyporesponsiveness to the antigen, termed “oral tolerance.” The first two outcomes are often referred to as “oral immunization,” although represent distinct phenomena. It appears that the clinical applications of oral antigen for the treatment of human conditions depend on the specific disease and the nature and dosages of proteins administered and might be benefitted from the use of synergists or mucosal adjuvants to enhance biologic effects.
Development of immune response to cow's milk proteins in infants receiving cow's milk or hydrolyzed formula
1995, The Journal of Allergy and Clinical Immunology
Background: Development of humoral and cellular immune responses to orally administered antigens in human beings is poorly understood, although antigen administration has been suggested as a treatment for hypersensitivity disorders and autoimmune diseases. Objective: The purpose of the study was to investigate the development of systemic immune response in infants fed with formula containing whole cow's milk proteins or hydrolyzed formula containing casein peptides. Methods: In a double-blind trial, 10 infants received cow's milk-based formula, and 10 infants received a casein hydrolysate formula until the age of 9 months. Blood samples were taken at the ages of 6, 9, and 12 months. Cellular responses were assessed by proliferation assay of peripheral blood mononuclear cells to cow's milk proteins (β-lactoglobulin, bovine serum albumin, and α-casein). Humoral responses to the same proteins were measured by ELISA for IgG antibodies. Results: Feeding infants with cow's milk-based formula induced systemic humoral and cellular responses to cow's milk proteins. T-cell response later declined, supporting the concept of oral tolerization. Exposure to cow's milk proteins after the age of 9 months resulted in depressed cellular and humoral responsiveness to these proteins. Conclusion: Our results support the view that induction of oral tolerance in human beings is an age-dependent phenomenon. (J ALLERGY CLIN IMMUNOL 1995;96:917-23.)
Evidence for spontaneous immunosuppression in autoimmune hepatitis
1995, Hepatology
Autoimmune hepatitis (AIH) runs a variable clinical course. Slow disease progression or even spontaneous remissions can be observed and suggest that the autoimmune process can, at least to a certain extent, be controlled by regulatory elements of the patient's own immune system. In experimental autoimmune hepatitis (EAH) spontaneous recovery is regularly observed and associated with antigen-specific and antigen-nonspecific suppression. The aim of the current study was to search for similar immunoregulatory phenomena in patients with AIH. We examined T-cell reactivity to soluble human liver antigens in 11 patients with active autoimmune hepatitis and 30 patients with other liver diseases (chronic viral hepatitis, primary biliary cirrhosis, fatty liver). T-cell reactivity to liver antigens was almost exclusively confined to the AIH patients. In 9 of these 11 patients we were able to compare the T-cell response in active untreated disease, directly after initiation of immunosuppressive therapy and in remission, at which point T-cell reactivity was found to be markedly reduced. Addition of irradiated peripheral blood cells from the active disease phase or the remission phase to the responding cells taken before treatment showed that in eight of the nine patients there was marked suppression of the liver-specific T-cell response by cells from the remission phase. Study of the in vivo immune responsiveness by giving a tetanus toxoid booster immunization to nine patients with active untreated AIH as well as healthy controls and patients with other liver diseases showed that none of the patients with AIH showed a response to the tetanus immunization, whereas almost all the other patients showed marked responses. Taken together these results show the presence of active suppression of T-cell autoreactivity in vitro in AIH and marked nonresponsiveness to in vivo challenge with an unrelated antigen, suggesting generalized spontaneous immunosuppression that is more pronounced in vivo than what can be measured in vitro. Spontaneous immunosuppression, however, is not sufficient to effectively suppress the disease process. Immunosuppressive therapy is required for remission induction, but is apparently helped by the patient's own immunoregulatory activity. These observations support the concept of peripheral control mechanisms being operative in patients with AIH, and these could be the basis for a more effective and specific immunotherapy of this condition in the future.
Non-sensitizing epicutaneous skin tests prevent subsequent induction of immune tolerance
1994, Journal of Investigative Dermatology
Oral administration of nickel or chromium to naive guinea pigs results in immune unresponsiveness to subsequent induction of allergic contact hypersensitivity. Such “oral tolerance” depends on the oral dose, is antigen specific, T-suppressor-cell mediated, and very persistent. In contrast, oral antigen administration to sensitized animals results at best in transient desensitization. Here we report that even non-sensitizing epicutaneous skin contacts prevented the subsequent induction of oral tolerance. These data support the view that primed T cells are less sensitive to suppressor T-cell function than naive T cells.
Oral induction of tolerance to nickel sensitization in mice
1993, Journal of Investigative Dermatology
Antigen contact via the alimentary tract prior to sensitization may result in systemic immunologic unresponsiveness (“oral tolerance”). The induction of oral tolerance seems an attractive strategy to combat undesired immune responses, such as allograft rejection and autoimmune and allergic diseases. We describe clear and reproducible sensitization to nickel in mice reared under nickel-free conditions. Hypersensitivity was induced by injecting nickel sulfate intradermally into the flank skin and elicited by injecting the metal salt into the pinnae of the cars. The effectiveness of orally induced hyporesponsiveness could be inferred from a low degree of hypersensitivity obtained with mice raised and maintained in cages with nickel-releasing covers and water nipples. This mouse model for the assay of nickel hypersensitivity was used for oral tolerance studies by administrating non-toxic doses of nickel sulfate in drinking water or intragastrically prior to sensitization. In these animals, the development of delayed-type hypersensitivity was suppressed in a dose-dependent way and the hyporesponsiveness could be transferred by CD8 cells. The antigen specificity of this oral tolerance could be demonstrated by the concomitant use of sensitization and challenge procedures for nickel and chromium. The hyper sensitivity assay described provides a versatile, highly reproducible experimental model to study immunoregulation of oral tolerance to clinically relevant metal allergens.

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¹: Current address: Kennedy Institute of Rheumatology, 6 Bute Gardens, London W6 7DW, UK.

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Could specific oral tolerance be a therapy for autoimmune disease?

Abstract

Immunol. Today

Cell. Immunol.

J. Neuroimmunol.

J. Invest. Dermatol.

Lancet

Clin. Immunol. Immunopathol.

Clin. Immunol. Immunopathol.

Lancet

Immunology

Clin. Exp. Immunol.

J. Immunol.

Neurology

J. Immunol.

Agents Actions

Clin. Exp. Immunol.

J. Immunol.

FASEB J.

FASEB J.

Immunology

Ann. NY Acad. Sci.

FASEB J.

J. Immunol.