Genetics of the Early and Late Response to Allergen Challenge

This study is currently recruiting participants.
Verified June 2012 by University of British Columbia
Sponsor:
Collaborators:
Allergy, Genes and Environment Network (AllerGen)
Networks of Centres of Excellence (NCE)
Information provided by (Responsible Party):
University of British Columbia
ClinicalTrials.gov Identifier:
NCT01113697
First received: April 28, 2010
Last updated: June 20, 2012
Last verified: June 2012
  Purpose

The investigators are investigating the early and late responses to allergen challenge. The research participants who the investigators will study (from three cohorts) will be part of independently-approved studies involving allergen challenge. Due to the uniqueness of the cohorts for novel genetic study, it is logical that the investigators should initially undertake hypothesis-generating experiments. The investigators will obtain blood samples from the participants, both pre-challenge and post-challenge. The investigators will determine gene expression and protein differences between these samples, and investigate if there are inherited genetic differences between individuals that may predict their specific responses to allergens.


Condition
Asthma
Allergic Rhinitis

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Prospective
Official Title: Molecular Mechanisms Involved in the Early and Late Responses to Allergen Challenge, in Asthmatic and Allergic Rhinitis Cohorts

Resource links provided by NLM:


Further study details as provided by University of British Columbia:

Biospecimen Retention:   Samples With DNA

Whole blood, plasma, white cells


Estimated Enrollment: 520
Study Start Date: August 2009
Estimated Study Completion Date: September 2014
Estimated Primary Completion Date: September 2014 (Final data collection date for primary outcome measure)
Groups/Cohorts
Clinical Investigator Collaborative (CIC) Asthma study cohort
Participants will be healthy volunteer research subjects with allergic asthma who will have an allergen inhalation challenge at CIC sites across Canada.
Western Red Cedar Asthma study cohort
Participants will be volunteer research subjects with Western Red Cedar asthma, who will have a plicatic acid inhalation challenge at The Lung Centre at Vancouver General Hospital.
Environmental Exposure Unit (EEU), Kingston General Hospital
Subjects will be over 19 years of age so that they qualify for studies involving allergen challenge.

Detailed Description:

Asthmatic and/or allergic rhinitis ('hay fever') individuals respond differently, but reproducibly, to allergen challenge. Some individuals develop an isolated early response while others also go on to develop a late response. In asthmatic individuals, airway narrowing represents the early phase of the asthmatic response to airway challenge; early phase onset can be detected within ten minutes of allergen inhalation, reaches a maximum within thirty minutes, and typically resolves within three hours. In 50-60% of allergic asthmatic adults, the early response is followed by the late phase asthmatic response, which usually starts between three and four hours after allergen inhalation challenge, and is characterized by cellular inflammation of the airway, increased lung tissue permeability, and mucus secretion. Thus, approximately half of allergic asthmatic subjects are 'dual responders' (developing both an early- and late-phase response following allergen inhalation challenge), 30-40% of allergic asthmatic adults develop an 'isolated early response', and <10% adults show an 'isolated late response'. In any given individual, the pattern of response is generally consistent. In allergic rhinitis individuals challenged by environmental exposure to pollen, equivalent differences exist in the proportions of subjects undergoing isolated early or dual phase nasal responses, with these responses measured by clinical end-points such as common symptoms of allergic rhinitis ('hay fever').

The role that inherited genetic variation might play in these differential early and late responses has so far been unexplored. However, recent experimental data in mouse models provide strong evidence that genetics could play an important role. When a specific intracellular pathway is disrupted by specific mouse gene-knockouts, this leads to the inhibition of a late response to allergen challenge, whilst maintaining the early response. The pathway is known as the Bcl10/Malt1 pathway, and it normally responds to allergen exposure by activating the expression of genes that code for pro-inflammatory proteins. The uncoupling of the late response from the early response suggests a possibility that genetic variation in genes involved in the human Bcl10/Malt1 pathway may influence the nature of the allergic response in humans. We will investigate whether there is a genetic basis for why some individuals develop an isolated early-phase response after allergen challenge whilst other individuals develop early- and late-phase responses (dual response).

We will recruit human allergic subjects undergoing experimentally-controlled allergen challenges. The specific airway responses of these individuals will be carefully and precisely measured, and blood samples will be collected just prior to, and two hours after, the allergen challenge. Due to the uniqueness of our cohorts for novel genetic study, it is logical that we should initially undertake hypothesis-generating experiments. Such experiments will involve the determination of differential changes in genome-wide gene expression in white blood cells and changes in the protein and lipid composition of the blood plasma, post-challenge compared to pre-challenge. We will then formulate and test hypotheses based on the results from these initial studies, as well as the specific following hypothesis: inherited genetic variation within the Bcl10/Malt1 pathway influence the early- and late-phase allergic response to allergen challenge.

Despite tremendous interest, the differences between the pathways leading to the dual response and those leading to the isolated early response are not completely understood. Understanding these differences is important for evaluating allergic diseases such as asthma and allergic rhinitis. In contrast to the more transient isolated early response, development of the late response is associated with the hallmark inflammatory features of chronic allergic disease. The combined cohorts represent a unique resource for the study of a fundamental physiologic response in allergy, and will provide genetic insight into new pathways for pharmacologic targeting in the treatment of chronic asthma and allergic rhinitis.

  Eligibility

Ages Eligible for Study:   19 Years to 55 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Sampling Method:   Probability Sample
Study Population

Asthmatic and/or allergic rhinitis ('hay fever') individuals, 19 years or older

Criteria

Inclusion Criteria:

  • participants will be healthy volunteer research subjects with allergic asthma, or
  • participants will be volunteer research subjects with Western Red Cedar asthma, or
  • participants will be healthy volunteer research subjects with allergic rhinitis (hay fever)
  • all participants will be over 19 years of age so that they qualify for studies involving allergen challenge
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01113697

Contacts
Contact: Scott J. Tebbutt, Ph.D Scott.Tebbutt@hli.ubc.ca

Locations
Canada, British Columbia
University of British Columbia Recruiting
Vancouver, British Columbia, Canada
Contact: Scott J. Tebbutt, Ph.D       Scott.Tebbutt@hli.ubc.ca   
Canada, Ontario
McMaster University Recruiting
Hamilton, Ontario, Canada
Contact: Scott J. Tebbutt, Ph.D       Scott.Tebbutt@hli.ubc.ca   
Queen's University Recruiting
Kingston, Ontario, Canada
Contact: Scott J. Tebbutt, Ph.D       Scott.Tebbutt@hli.ubc.ca   
Canada, Saskatchewan
University of Saskatchewan Recruiting
Saskatoon, Saskatchewan, Canada
Contact: Scott J. Tebbutt, Ph.D       Scott.Tebbutt@hli.ubc.ca   
Canada
Laval University Recruiting
Quebec, Canada
Contact: Scott J. Tebbutt, Ph.D       Scott.Tebbutt@hli.ubc.ca   
Sponsors and Collaborators
University of British Columbia
Allergy, Genes and Environment Network (AllerGen)
Networks of Centres of Excellence (NCE)
Investigators
Principal Investigator: Scott J. Tebbutt, Ph.D University of British Columbia
Study Director: Gail M. Bauvreau, Ph.D McMaster University
Study Director: Anne K. Ellis, MD Queen's University
Study Director: Christopher R. Carlsten, MD University of British Columbia
Study Director: Danuta Radzioch, Ph.D McGill University
  More Information

Publications:
Responsible Party: University of British Columbia
ClinicalTrials.gov Identifier: NCT01113697     History of Changes
Other Study ID Numbers: H09-02114
Study First Received: April 28, 2010
Last Updated: June 20, 2012
Health Authority: Canada: Health Canada

Keywords provided by University of British Columbia:
allergen challenge
blood draw
gene expression analysis
protein analysis
genetics

Additional relevant MeSH terms:
Asthma
Rhinitis
Bronchial Diseases
Respiratory Tract Diseases
Lung Diseases, Obstructive
Lung Diseases
Respiratory Hypersensitivity
Hypersensitivity, Immediate
Hypersensitivity
Immune System Diseases
Nose Diseases
Respiratory Tract Infections
Otorhinolaryngologic Diseases

ClinicalTrials.gov processed this record on April 17, 2014