The worldwide prevalence, morbidity and mortality of allergic asthma and associated cost are increasing. Moreover, asthma is the most common chronic disease reported in children, limiting the activities of many of then. In addition, allergi sensitization in childhood is a major predictor of chronic-relapsing asthma in adulthood. The pathophysiological features of chronic inflammation in allergic asthma are primarily the result of the aberrant activation and expansion of pathogenic T-helper 2 (TH2) immune responses to common environmental allergens. Thus, therapeutics that target the development, maintenance or function of allergen- specific TH2 cells could be used to treat asthma-associated pathology. Unfortunately, there are significant gaps in our understanding of mechanisms that initiate and regulate TH2 responses to inhaled allergens, which complicates the identification of therapeutic modalities that specifically block TH2 responses. Our preliminary data suggest that TH2 type-T follicular helper (TFH)-like cells represent TH2 memory precursors that persist long-term and convert into TH2 cell effector upon allergen recall responses. Moreover, our data suggest that the requirements to induce TH2 type-TFH-like/memory precursors vary with the age of the allergen sensitization and the levels of exposure to endotoxin. Finally, our data suggest that the age-related variances are, at least in part, mediated by differences in dendritic cell (DC) intrinsc response to toll-like receptor (TLR)-mediated activation. Thus, we hypothesize that allergen sensitization induce DC-mediated priming of TH2-type TFH cells that full develop and survive as allergen-specific TH2-type memory cells for extended periods of time after interaction with B cells within the follicle. After allergen re-exposure, allergen-specific TH2-type TFH/memory cells differentiate into short-term effector-TH2 cells and home into the lung to cause pathology. Importantly, we hypothesize that the process of allergen sensitization is more efficient in childhood due to the fact that DCs differently respond to environmental endotoxin levels and induce enhanced priming of HDM-specific pre-TH2- type TFH cells and/or TH2-type TFH cells display an enhanced survival/maintenance in childhood. In this proposal we will test this model and evaluate how allergen-bearing DCs initiate TFH cell commitment and imprint a TH2-cytokine profile in adults and infants and how microbial exposure differentially affects this process. We will study the factors required for the long-term maintenance of allergen-specific TH2 type-TFH- like/memory cells and explore the plasticity of TH2-type TFH-like cell compartment. Finally, we will evaluate the potential clinical benefits of TFH-cell antagonist to deplete HDM-specific memory TFH cells and treat allergen- specific TH2 responses. We believe that our work will contribute to our understanding of how allergen TH2-type cell responses are initiated and maintained and ultimately reveal new information about potential targets for therapeutic intervention in patients with asthma.
Allergic asthma is a chronic inflammatory lung disease initiated and directed by T helper cells type 2 (TH2). The mechanism involved in generation of TH2 responses to inhaled allergens is largely unknown. This proposal will determine whether co-exposure to allergens and environmental endotoxin or other microbial products in childhood can influence development of long-lived memory type-2 T cells and therefore asthma severity in adults.
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