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The CD28/CTLA-4-B7 signaling pathway is involved in both allergic sensitization and tolerance induction to orally administered peanut proteins

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Author: Wijk, F. van · Nierkens, S. · Jong, W. de · Wehrens, E.J.M. · Boon, L. · Kooten, P. van · Knippels, L.M.J. · Pieters, R.
Type:article
Date:2007
Institution: TNO Kwaliteit van Leven
Source:Journal of Immunology, 11, 178, 6894-6900
Identifier: 239988
Keywords: Nutrition · Toxicology and Applied Pharmacology · Chymase · Cytotoxic T lymphocyte antigen 4 · Immunoglobulin G1 · Immunoglobulin G2a · Peanut protein · Protein · Mouse · Peanut allergy · Sensitization · Signal transduction · T lymphocyte · T lymphocyte activation · Administration, Oral · Allergens · Animals · Antibodies, Blocking · Antigens, CD · Antigens, CD28 · Antigens, CD80 · Antigens, Differentiation · Arachis hypogaea · Cells, Cultured · Disease Models, Animal · Food Hypersensitivity · Immune Tolerance · Immunoconjugates · Immunoglobulin E · Ligands · Mice · Plant Extracts · Plant Proteins · Signal Transduction

Abstract

Dendritic cells are believed to play an essential role in regulating the balance between immunogenic and tolerogenic responses to mucosal Ags by controlling T cell differentiation and activation via costimulatory and coinhibitory signals. The CD28/CTLA-4-CD80/CD86 signaling pathway appears to be one of the most important regulators of T cell responses but its exact role in responses to orally administered proteins remains to be elucidated. In the present study, the involvement of the CD28/CTLA-4-CD80/CD86 costimulatory pathway in the induction of allergic sensitization and oral tolerance to peanut proteins was investigated. In both an established C3H/HeOuJ mouse model of peanut hypersensitivity and an oral tolerance model to peanut, CB28/CTLA-4-CB80/CD86 interactions were blocked using the fusion protein CTLA-4Ig. To examine the relative contribution of CD80- and CD86-mediated costimulation in these models, anti-CD80 and anti-CD86 blocking Abs were used. In the hypersensitivity model, CTLA-4Ig treatment prevented the development of peanut extract-induced cytokine responses, peanut extract-specific IgG1, IgG2a, and IgE production and peanut extract-induced challenge responses. Blocking of CD80 reduced, whereas anti-CD86 treatment completely inhibited, the induction of peanut extract-specific IgE. Normal tolerance induction to peanut extract was found following CTLA-4Ig, anti-CD86, or anti-CD80 plus anti-CD86 treatment, whereas blockade of CB80 impaired the induction of oral tolerance. We show that CD28/CTLA-4-CD80/CD86 signaling is essential for the development of allergic responses to peanut and that CD86 interaction is most important in inducing peanut extract-specific IgE responses. Additionally, our data suggest that CD80 but not CD86 interaction with CTLA-4 is crucial for the induction of low dose tolerance to peanut. Copyright © 2007 by The American Association of Immunologists, Inc.