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

NCT02779881 | Completed

• 1 other identifier: 1-14
• Study Type: observational
• Target: 40
• Locations: 1 country
• Sites: 1

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.

Conditions

Cow's Milk Allergy

Outcome Measures

Primary Outcomes (1)

• DNA demethylation (rate, in %) of the Treg-specific-demethylated-region (TSDR) of FoxP3

  At enrollment

Study Arms (4)

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

Interventions

Extensively hydrolyzed casein formula plus LGG DIETARY_SUPPLEMENT

Subjects outgrown cow's milk allergy with formula+probiotic

Eligibility Criteria

• Age: 3 Months - 18 Months
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)
• 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.

You may qualify if:

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

You may not qualify if:

• 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

Sponsors & Collaborators

• Federico II University: lead

Study Sites (1)

University of Naples Federico II

Naples, 80131, Italy

Location

Related Publications (1)

• Paparo L, Nocerino R, Cosenza L, Aitoro R, D'Argenio V, Del Monaco V, Di Scala C, Amoroso A, Di Costanzo M, Salvatore F, Berni Canani R. Epigenetic features of FoxP3 in children with cow's milk allergy. Clin Epigenetics. 2016 Aug 12;8:86. doi: 10.1186/s13148-016-0252-z. eCollection 2016.

  PMID: 27525046 DERIVED

MeSH Terms

Conditions

Milk Hypersensitivity

Condition Hierarchy (Ancestors)

Food Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases

Study Design

• Study Type: observational
• Observational Model: CASE CROSSOVER
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD, PhD

Study Record Dates

• First Submitted: May 16, 2016
• First Posted: May 23, 2016
• Study Start: December 1, 2012
• Primary Completion: April 1, 2014
• Study Completion: April 1, 2014
• Last Updated: May 23, 2016

Record last verified: 2016-05

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)