title: Oral tolerance induction by partially hydrolyzed whey protein in mice is associated with enhanced numbers of Foxp3+ regulatory T-cells in the mesenteric lymph nodes.
abstract: BACKGROUND
  Hypoallergenic formulas are considered a good option for infants at risk for cow's milk allergy. The aim of this animal study was to investigate whether whey hydrolyzates (WH) have the capacity to induce oral tolerance to whey.
  
  
  METHODS
  Whey, partial or extensive WH was given via gavages to naïve mice prior to oral whey sensitization using cholera toxin as an adjuvant. The acute allergic skin response, mouse mast cell protease-1 (mMCP-1), whey-specific IgE, IgG(1) and effector Th2-cells, Th1-cells, and Foxp3(+) regulatory T-cells were determined in the mesenteric lymph nodes (MLN). MLN cells from tolerized mice were adoptively transferred to naïve recipient mice prior to whey sensitization.
  
  
  RESULTS
  In contrast to the extensive WH, pre-treatment of naïve mice with whey or partial WH reduced the acute allergic skin response and mast cell degranulation after whey challenge. However, only treatment with whey prevented the generation of serum-specific IgE/IgG(1) . In partial WH tolerized mice, Foxp3(+) regulatory T-cell numbers in the MLN were increased compared to whey-sensitized mice. Both whey and partial WH treatment showed a tendency toward a decreased number of effector Th2-cells. Transfer of MLN cells from tolerized mice protected recipient mice from developing an acute allergic skin response.
  
  
  CONCLUSIONS
  These results show that partial WH with limited sensitizing properties reduced the effector response upon whey challenge. This effect is transferable using MLN cells and was associated with enhanced Foxp3(+) regulatory T-cell numbers in the MLN. Partial WH retained the capacity to induce active immune suppression in mice which may be relevant for allergy prevention.
authors.affiliation: Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands. e.c.a.m.vanesch@uu.nl
authors.forename: Betty C A M
authors.initials: BC
authors.lastname: van Esch
authors.forename: Bastiaan
authors.initials: B
authors.lastname: Schouten
authors.forename: Sander
authors.initials: S
authors.lastname: de Kivit
authors.forename: Gerard A
authors.initials: GA
authors.lastname: Hofman
authors.forename: Léon M J
authors.initials: LM
authors.lastname: Knippels
authors.forename: Linette E M
authors.initials: LE
authors.lastname: Willemsen
authors.forename: Johan
authors.initials: J
authors.lastname: Garssen
mesh_terms: D000284:Administration, Oral; D000485:Allergens / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry; D000818:Animals; D002478:Cells, Cultured; D053818:Chymases / Q000378:metabolism; D003888:Desensitization, Immunologic; D004195:Disease Models, Animal; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D007108:Immune Tolerance; D007073:Immunoglobulin E / Q000097:blood; D008198:Lymph Nodes / Q000473:pathology; D008643:Mesentery / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D016269:Milk Hypersensitivity / Q000188:drug therapy / Q000276:immunology*; D008894:Milk Proteins / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D058408:Th1-Th2 Balance; D000067816:Whey Proteins
chemical_list: D000485:Allergens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D008894:Milk Proteins; D000067816:Whey Proteins; D007073:Immunoglobulin E; D053818:Chymases; C509230:Mcpt1 protein, mouse