Mechanisms of Oral Tolerance

Garside, Paul; Mowat, Allan Mcl.

doi:10.1615/critrevimmunol.v17.i2.10

Cited by 77 publications

(45 citation statements)

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“…Soluble protein Ags encountered through the respiratory or gastrointestinal tracts do not elicit strong systemic immune responses, but induce a state of Ag-specific unresponsiveness that is commonly refered to as mucosal tolerance (33). The down-regulation of immune responses in the gut mucosa is relatively well defined and appears to rely on at least three distinct mechanisms: clonal deletion (34), anergy (35,36), and active suppression mediated by regulatory cells secreting TGF-␤ and Th2-like cytokines (23,33,37).…”

Section: Discussionmentioning

confidence: 99%

“…The down-regulation of immune responses in the gut mucosa is relatively well defined and appears to rely on at least three distinct mechanisms: clonal deletion (34), anergy (35,36), and active suppression mediated by regulatory cells secreting TGF-␤ and Th2-like cytokines (23,33,37). In contrast, the immunological processes underlying the natural immunity to inhaled proteins are poorly defined.…”

Section: Discussionmentioning

confidence: 99%

“…Intranasal or oral administration of a single immunodominant peptide derived from the house dust mite protein Der p 1, when given before immunization with the whole protein, can induce peripheral tolerance (49,50). Systemic or mucosal administration of short dominant epitopes derived from Der p 1 (30,31), Bet v 1 (32), or Fel d 1 (33) led to the induction of T cell tolerance to the whole allergen in several murine experimental models, in prophylactic settings only, however. The clinical efficacy of such an approach has been recently investigated in humans (16,34).…”

Section: Discussionmentioning

confidence: 99%

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Inducing Tolerance by Intranasal Administration of Long Peptides in Naive and Primed CBA/J Mice

Astori

Garnier

Kettner

et al. 2000

The Journal of Immunology

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To assess the capacity of a peptide-based immunotherapy to induce systemic tolerance via the nasal route, we designed three long overlapping peptides of 44–60 aa covering the entire sequence of phospholipase A2 (PLA2), a major bee venom allergen. Both prophylactic and therapeutic intranasal administrations of long peptides to PLA2-hypersensitive CBA/J mice induced specific T cell tolerance to the native allergen. In prophylactic conditions, this tolerance was marked by a suppression of subsequent specific IgE response, whereas the therapeutic approach in presensitized mice induced a more than 60% decrease in PLA2-specific IgE. This decline was associated with a shift in the cytokine response toward a Th1 profile, as demonstrated by decreased PLA2-specific IgG1 and enhanced IgG2a levels, and by a decline in the specific IL-4/IFN-γ ratios. T cell transfer from long peptide-tolerized mice to naive animals abrogated the expected anti-PLA2 IgE and IgG1 Ab response, as well as specific T cell proliferation, but enhanced specific IgG2a response upon sensitization with PLA2. These events were strongly suggestive of a clonal anergy affecting more profoundly Th2 than the Th1 subsets. In conclusion, these results demonstrate that allergen-derived long peptides delivered via the nasal mucosa may offer an alternative to immunotherapy with native allergens without the inherent risk of systemic anaphylactic reactions. Moreover, long peptides, in contrast to immunotherapy strategies based on short peptides, have the advantage of covering all potential T cell epitopes, and may represent novel and safe tools for the therapy of allergic diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Inducing Tolerance by Intranasal Administration of Long Peptides in Naive and Primed CBA/J Mice

Astori

Garnier

Kettner

et al. 2000

The Journal of Immunology

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“…Mucosal tolerance was discovered early in the 20 th century in models of delayed-type and contact hypersensitivity reactions in guinea pigs, but the mechanisms of tolerance remained ill-defined until the era of modern immunology. The use of cell separation techniques, tests for production of cytokines and transgenic models in which antigen-specific T cells can be tracked in vivo have gradually elucidated mechanisms of mucosal tolerance [3,4]. It has become evident that antigen administration via mucosal routes can result in distinct types of tolerance depending on the route of administration and dose of antigen.…”

Section: Mucosal Tolerance: Definition and Mechanismsmentioning

confidence: 99%

“…Repeated exposure to antigen in each case is able to induce regulatory T cells, but the nature of these cells differs, depending on the route and form of antigen. While regulatory cells induced by oral antigen are CD4 T cells [3,12] and express T cell receptors consisting of αβ-heterodimers, in the case of naso-respiratory antigen the regulatory cells belong to a class of CD8 T cells expressing T cell receptors consisting of γδ heterodimers (i.e. γδ T cells).…”

Section: Mucosal Tolerance: Definition and Mechanismsmentioning

confidence: 99%

Mucosal Tolerance to Prevent Type 1 Diabetes: Can the Outcome Be Improved in Humans?

Hänninen

Harrison²

2004

Rev Diab Stud

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Selective tolerization of Th1-like cells after nasal administration of a cholera toxoid-LACK conjugate

et al. 1998

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Recent reports have suggested that after infection of BALB/c mice with Leishmania major, CD4 + T cells responding to a single antigen, LACK (Leishmania homologue of receptors for activated C kinase), drive the differentiation of other responding T cells to the Th2 phenotype and so allow lesion development to occur. Transgenic mice expressing LACK in the thymus are tolerant to LACK and thus resolve infection with L. major. The oral administration of soluble protein to mice has been shown to result in the peripheral tolerance of antigen-specific CD4 + T cells. We therefore sought to tolerize LACK reactive T cells in non-transgenic BALB/c mice in order to determine the effectiveness of this tolerization approach as an alternative to standard vaccination protocols againist L. major infection. Surprisingly, oral or nasal administration of up to 8 mg of recombinant LACK did not affect the outcome of infection. We therefore conjugated LACK to cholera toxin g subunit (CTB-LACK) which has previously been shown to improve the effectiveness of oral tolerance to conjugated antigens. Nasal administration of as little as 12 ? g of CTB-LACK effectively diminished the capacity of mice to mount a subsequent proliferative response to LACK and further delayed the onset of lesion development in infected mice. However, pretreatment with CTB-LACK did not prevent the eventual onset and progression of disease in these mice. An examination of cytokine responsiveness to LACK after tolerization with CTB-LACK revealed that while the Th1 response to LACK was suppressed, Th2 cytokine production was unaffected. Similar experiments using an ovalbumin-CTB conjugate suggested that this selective tolerance of Th1 cells was not specific to the LACK protein but may be an effect common to CTB-conjugated proteins.

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Mechanisms of Oral Tolerance

Cited by 77 publications

References 0 publications

Inducing Tolerance by Intranasal Administration of Long Peptides in Naive and Primed CBA/J Mice

Inducing Tolerance by Intranasal Administration of Long Peptides in Naive and Primed CBA/J Mice

Mucosal Tolerance to Prevent Type 1 Diabetes: Can the Outcome Be Improved in Humans?

Selective tolerization of Th1-like cells after nasal administration of a cholera toxoid-LACK conjugate

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