Rebecca Gruchalla, M.D., Ph.D.
Associate Professor of Internal Medicine

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Project 1 Allergen Immunotherapy (AIT) Combined with Inhaled Corticosteroid (ICS) Therapy in Mild to Moderate Persistent Asthma in Children: Immunologic Mechanisms of Action

Objectives of Study: AIT has been used for treatment of allergic asthma in children, and, like ICS, decreases not only mast cell recruitment into the airway, but also bronchial eosinophil counts and granule protein content (e.g. ECP concentrations). In addition, allergen-specific IgG levels have been shown to rise in allergic patients who receive AIT. In contrast to ICS, AIT may also modulate allergen-specific immune activity. For example, there appears to be a shift in allergen-specific T lymphocyte cytokine profiles from a Th2 polarized response to a Th1 profile. It is proposed that, as a consequence of decreased IL-5 production, eosinophil recruitment to the lungs is inhibited. Since the clinical effects of AIT persist following its discontinuation , it is possible that the immunomodulatory effects produced by this form of therapy will lead to a persistent alteration in Th1/Th2 cytokine balance and, as a consequence, produce prolonged modulation of allergen-driven inflammatory activity. The objectives of the proposed studies are to determine the immune-based mechanisms by which both ICS and AIT modulate selected allergic inflammatory activities and to define differences between ICS and AIT effects on these parameters.
Specific aims: 1) To evaluate the hypothesis that improved asthma control with AIT is related to an increase in allergen-specific Th1 activity by PBMC (i.e., increased IFN-( production) with resultant decreased Th2 cytokine production (i.e., IL-4, -5, and -13) and to compare these effects with those found with ICS; 2) To test the hypothesis that AIT, but not ICS, will lead to a long-term decrease in eosinophils in the peripheral blood through prolonged inhibition of Th2-cell production of IL-5, and that this decrease in eosinophils will be associated with a reduction in bronchial hyperresponsiveness.
Significance: The proposed studies are designed to elucidate the mechanisms by which allergen immunotherapy may modify the asthma phenotype. They will address whether an immunomodulatory agent, i.e., AIT, modulates T cell cytokine profiles of allergic asthmatic children and, if it does, we will determine the persistence of this effect and its relationship to the clinical effects on asthma.

Project 2 Community Leadership in Preventing Asthma - CLIP Asthma

Objectives of the Study: Our overall hypothesis is that environmental allergen exposures in school environments contribute to the asthma-associated morbidity demonstrated by inner-city asthmatic children. There are two primary objectives for the proposed project: to identify allergens in school environments that contribute to asthma-associated morbidity (evaluative component) and to collaborate with relevant stakeholders to discuss and to develop community-responsive solutions based on the study's findings (community-responsive component). In order to accomplish our goals, a partnership will be established with leaders in the faith-health community and these individuals will be actively involved in all aspects of the research process.
Specific aims: 1) To create a collaborative partnership between researchers and leaders from community faith-based organizations that allows the community leaders to participate in each step of the research process and to contribute to the interpretation of the study findings in the context of the target community; 2) To determine if asthma-associated morbidity (lung function, respiratory symptoms and medication use) among inner city asthmatic children is related to specific allergen levels in the indoor school environment; 3) To develop community-responsive solutions to problems identified as a result of the research teams' investigation.
Significance: The significance of the proposed project is important from a number of respects. First, this will be one of the first studies to examine multiple allergens simultaneously in the inner city school environment. Second, this project will be novel in that we propose to measure asthma symptoms and lung function in relationship to multiple indoor allergens in the school. Third, this will be one of the first studies to evaluate the relationship between asthma morbidity and allergens in the school environment. Fourth, unlike previous studies, CLIP Asthma will employ a community-based participatory approach by thoroughly involving churches as community representatives in all stages of the research process. The CLIP Asthma plan is, therefore, more than community-placed outreach activity -- it is designed to be community-driven and responsive by identifying and incorporating unique cultural factors into the proposed research strategies in order to increase acceptability, use, and adherence among the target population.