title: CTLA-4 signaling regulates the intensity of hypersensitivity responses to food antigens, but is not decisive in the induction of sensitization.
abstract: Although food allergy has emerged as a major health problem, the mechanisms that are decisive in the development of sensitization to dietary Ag remain largely unknown. CTLA-4 signaling negatively regulates immune activation, and may play a crucial role in preventing induction and/or progression of sensitization to food Ag. To elucidate the role of CTLA-4 signaling in responses to food allergens, a murine model of peanut allergy was used. During oral exposure to peanut protein extract (PPE) together with the mucosal adjuvant cholera toxin (CT), which induces peanut allergy, CTLA-4 ligation was prevented using a CTLA-4 mAb. Additionally, the effect of inhibition of the CTLA-4 pathway on oral exposure to PPE in the absence of CT, which leads to unresponsiveness to peanut Ag, was explored. During sensitization, anti-CTLA-4 treatment considerably enhanced IgE responses to PPE and the peanut allergens, Ara h 1, Ara h 3, and Ara h 6, resulting in elevated mast cell degranulation upon an oral challenge. Remarkably, antagonizing CTLA-4 during exposure to PPE in the absence of CT resulted in significant induction of Th2 cytokines and an elevation in total serum IgE levels, but failed to induce allergen-specific IgE responses and mast cell degranulation upon a PPE challenge. These results indicate that CTLA-4 signaling is not the crucial factor in preventing sensitization to food allergens, but plays a pivotal role in regulating the intensity of a food allergic sensitization response. Furthermore, these data indicate that a profoundly Th2-biased cytokine environment is insufficient to induce allergic responses against dietary Ag.
authors.affiliation: Institute for Risk Assessment Sciences, Immunotoxicology, Utrecht University, PO Box 80176, NL 3508 TD Utrecht, The Netherlands. F.vanWijk@iras.uu.nl
authors.forename: Femke
authors.initials: F
authors.lastname: van Wijk
authors.forename: Sanne
authors.initials: S
authors.lastname: Hoeks
authors.forename: Stefan
authors.initials: S
authors.lastname: Nierkens
authors.forename: Stef J
authors.initials: SJ
authors.lastname: Koppelman
authors.forename: Peter
authors.initials: P
authors.lastname: van Kooten
authors.forename: Louis
authors.initials: L
authors.lastname: Boon
authors.forename: Léon M J
authors.initials: LM
authors.lastname: Knippels
authors.forename: Raymond
authors.initials: R
authors.lastname: Pieters
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000485:Allergens / Q000276:immunology*; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology* / Q000378:metabolism; D060908:CTLA-4 Antigen; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D007073:Immunoglobulin E / Q000097:blood; D008407:Mast Cells / Q000276:immunology / Q000378:metabolism; D051379:Mice; D021183:Peanut Hypersensitivity / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000485:Allergens; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D016207:Cytokines; D007073:Immunoglobulin E