Promoting Tolerance to Common Allergens in High-Risk Children: Global Prevention of Asthma in Children (GPAC) Study

Principal Investigator

Patrick Holt | University of Western Australia | Perth, AUS

Peter Sly | Telethon Institute for Child Health Research | Perth, AUS

Locations

Telethon Institute for Child Health Research | Perth, AUS

Royal Children's Hospital | Melbourne, AUS

Mount Sinai School of Medicine | New York, NY

Karolinska Institute Allergy Center | Stockholm, SWE

Charite-Universitatsmedizin | Berlin, DE

Study Code

ITN025AD

Study Status

Completed

Abstract

Objectives : To reduce the frequency of allergic sensitization and expression of allergic disease (in particular atopic asthma) amongst children at high genetic risk of asthma/atopy.

Approach: Two hundred children aged between 18 and 30 months with a history of AD or food allergy but without sensitization to inhalants in treatment mix as demonstrated by SPT and IgE specific antibodies and whose biological mother or father, or one sibling has a well-documented history of atopy (AD, allergic rhinitis or asthma) will be recruited. They will be randomized to receive sublingual drops, containing either allergen (house dust mite, timothy grass & cat) or placebo, daily for 12 months and followed for three years after finishing treatment. Development of allergen sensitization (IgE/IgG, T-cell responses) and asthma (clinical history & exam, lung function & bronchodilator response) will be monitored. Outcome assessments occur at 12 months (50% reduction in allergen sensitization) and 3 years (50% reductions in allergen sensitization, Th-2 responses and asthma).

Rationale: Key findings underpinning this proposal are:

  1. Atopic asthma in childhood is a two stage process, comprising initial sensitization to inhalant allergens, and subsequent inflammatory damage to growing lung tissues leading to altered respiratory function(s)
  2. Atopic sensitization to inhalants is associated with development of Th2-associated memory as opposed to weak Th1-like memory in "tolerant" nonatopics
  3. This T-memory is programmed during the preschool years
  4. The earlier that T-cell sensitization occurs, the more severe are asthma-associated sequelae in later childhood
  5. Parental history of asthma/allergy together with personal history of food allergy/AD identifies children at high risk (HR) of developing persistent atopy/asthma

The experimental literature suggests that sensitization to inhalants occurs as a result of failure of normal mucosal tolerance processes which are initiated during early exposures. Our forerunner studies in humans indicate that the life phase in which this occurs is infancy/early childhood. Whilst the underlying tolerance mechanism(s) remain poorly understood, a key feature involves generation of regulatory T-cells in LN draining the oronasal/pharyngeal mucosa, which receive the bulk of aeroallergenic stimulation.

Our earlier animal studies indicate that the efficiency of this process is directly related to the intensity of antigen stimulation, inferring that protection against sensitization via mucosal tolerance can potentially be enhanced therapeutically. Indirect support for this comes from Platts-Mills data suggesting that intense cat exposure induces split tolerance involving IgE-selective suppression with concomitant preservation of IgG. This (subclinical) response phenotype is identical to that consistently reported by our lab from animal models.

Significance: If successful, this approach has potential to reverse the continuing upward spiral in allergy/asthma prevalence in both the pediatric and adult segments of the population. The underlying principles involve enhancement of natural "mucosal tolerance" processes which normally protect against allergic sensitization to inhalants.

Protocol Summary: Double-blind randomized controlled trial of sublingual immunotherapy daily for 12 months in 200 children at high risk of developing allergies and asthma with follow-up for 3 years post treatment. Outcomes: 50% reduction in IgE and Th2 responses to allergens given and 50% reduction in asthma.

Current Status : (as of 2/17/2010) Treatment of the first 50 children (half active/half placebo) was completed in July 2008 and no serious adverse events have been encountered.  Allergen-specific antibody titres are being determined at regular intervals in the subjects.  The investigators remain blinded to these results, which are being monitored independently by the ITN.  Recruitment of futher trial subjects remains suspended until evidence of treatment-related modulation of allergen-specific antidbody titres is provided from the ongoing testing.

Articles

DOI: 

http://dx.doi.org/10.1016/j.jaci.2013.04.049

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PMID: 

23768574

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PMCID: 

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PubMed

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