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Epigenetic Features of FoxP3 in Children With Cow's Milk Allergy

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02779881
Recruitment Status : Completed
First Posted : May 23, 2016
Last Update Posted : May 23, 2016
Information provided by (Responsible Party):
Roberto Berni Canani, Federico II University

Brief Summary:

Epigenetic mechanisms have been implicated in the pathogenesis of food allergy. The investigators previously demonstrated that tolerance acquisition in children with Immunoglobulin E- (IgE) mediated cow's milk allergy (CMA) is driven by epigenetic modulation of the Th1 and Th2 cytokine genes. A regulatory T cell (Treg) suppressive phenotype, characterized by stable expression of the transcription factor "Forkhead box Protein 3" (FoxP3), plays a pivotal role in food tolerance. FoxP3 mRNA expression is lower in children with atopic asthma or IgE-mediated food allergy than in healthy children. FoxP3 stable expression requires full CpG demethylation of its transcriptional regulatory regions, and, moreover, hypermethylation of the FoxP3 gene has been associated with reduced Treg function and allergy.

DNA methylation is a biologically and chemically stable epigenetic modification that locks in long-term gene expression patterns. The demethylation status of FoxP3 at a highly conserved region within the Treg-specific-demethylated-region (TSDR), a CpG-rich, located on the 2nd conserved non-coding sequence of FoxP3 (CNS2), is restricted to Tregs. Transcriptional activity of the TSDR is essentially determined by its methylation status : it is completely inactive in its methylated state, but when the TSDR is demethylated, transcription factors such as Ets-1 and Creb can bind to the TSDR. TSDR demethylated and open chromatin conformation in the Foxp3 locus leads to stable phenotype differentiated Foxp3+ Treg. FoxP3 TSDR demethylation in peripheral blood mononuclear cells (PBMCs) has been associated with reduced atopic sensitization and asthma in children. Epigenetic regulation of antigen-induced T-cell subsets may predict a state of immune tolerance in food allergy. Indeed, DNA methylation of the FoxP3 gene in Tregs decreased during oral tolerance acquisition in patients with peanut allergy undergoing oral immunotherapy. The aim of this study was to evaluate further the epigenetic regulation of FoxP3 gene in children with IgE-mediated CMA.

Condition or disease Intervention/treatment
Cow's Milk Allergy Dietary Supplement: Extensively hydrolyzed casein formula plus LGG

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Study Type : Observational
Actual Enrollment : 40 participants
Observational Model: Case-Crossover
Time Perspective: Cross-Sectional
Study Start Date : December 2012
Actual Primary Completion Date : April 2014
Actual Study Completion Date : April 2014

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Allergy
Drug Information available for: Casein

Group/Cohort Intervention/treatment
Healthy controls
Healthy controls
Children at diagnosis of cow's milk allergy
Children at diagnosis of cow's milk allergy
Subjects outgrown cow's milk allergy with formula+probiotic
Tolerant with extensively hydrolyzed casein formula with Lactobacillus rhamnosus GG
Dietary Supplement: Extensively hydrolyzed casein formula plus LGG
Subjects outgrown cow's milk allergy assuming other formulas
Subjects tolerant with other formulas

Primary Outcome Measures :
  1. DNA demethylation (rate, in %) of the Treg-specific-demethylated-region (TSDR) of FoxP3 [ Time Frame: At enrollment ]

Information from the National Library of Medicine

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Ages Eligible for Study:   3 Months to 18 Months   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population

IgE-mediated CMA children (aged 3 to 18 months) consecutively referred to the tertiary Pediatric Allergy Center for oral food challenge.

During the same study period, consecutive healthy children, not at risk of atopic disorders (namely, those without a first-degree relative affected by an atopic disorder), attending the Center because of minimal surgical procedures served as a control group.

A venous blood sample (4 ml) was obtained from all patients after oral challenge.


Inclusion Criteria:

  • IgE-mediated CMA children (aged 3 to 18 months)

Exclusion Criteria:

  • allergic disorders or food allergies other than cow's milk allergy
  • eosinophilic disorders of the gastrointestinal tract
  • food protein-induced enterocolitis syndrome
  • concomitant chronic systemic diseases
  • congenital cardiac defects
  • active tuberculosis
  • autoimmune diseases
  • immunodeficiency
  • chronic inflammatory bowel diseases
  • celiac disease
  • cystic fibrosis
  • metabolic diseases
  • lactose intolerance
  • malignancy
  • chronic pulmonary diseases
  • malformations of the gastrointestinal tract

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02779881

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University of Naples Federico II
Naples, Italy, 80131
Sponsors and Collaborators
Federico II University
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: Roberto Berni Canani, MD, PhD, Federico II University Identifier: NCT02779881    
Other Study ID Numbers: 1-14
First Posted: May 23, 2016    Key Record Dates
Last Update Posted: May 23, 2016
Last Verified: May 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Additional relevant MeSH terms:
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Milk Hypersensitivity
Immune System Diseases
Food Hypersensitivity
Hypersensitivity, Immediate
Chelating Agents
Sequestering Agents
Molecular Mechanisms of Pharmacological Action