Prophylaxis of atopy and asthma in children

Principal Investigator: Patrick G. Holt, University of Western Australia, Perth, AUS

Abstract | Investigators | Background

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.

Participating Investigators

	Patrick G. Holt, University of Western Australia, Perth AUS
	Peter Sly, University of Western Australia, Perth, AUS
	Bengt Bjorksten, Karolinska Institute, Stockholm, SWE
	Ulrich Wahn, Berlin Humboldt University , Germany
	Richard Loh, Princess Margaret Hospital for Children, Perth, AUS

Background Articles

On early sensitization to allergens and development of respiratory symptoms - Clin Exp Allergy [go]