Allergic asthma stems from inappropriate immune responses to inhaled antigens. Thus, to prevent or treat allergic asthma, it is important to identify the cellular and molecular mechanisms that initially give rise to allergic sensitization, as well as the pathways that regulate allergic inflammation once it has begun. Accordingly, our laboratory uses a mouse model of asthma in which the animals are senstized to inhaled allergens. For example, ovalbumin (OVA) is delivered to the airway together with various adjuvants. Such adjuvants include ligands of various toll-like receptors (TLRs), including lipopolysaccharide (LPS) and bacterial flagellin. Pulmonary dendritic cells lining the airway epithelium take up OVA and migrate to draining thoracic lymph nodes to present allergen-derived peptides to nave T cells. We have found that this method of sensitization primes a qualitatively different type of immune response than the more conventional method of sensitization involving intraperitoneal (i.p.) injections of OVA complexed with aluminum hydroxide (alum). Thus, sensitization through the airway, but not through the peritoneum, can induce robust T helper (Th)17 responses. These Th17 cells produce IL-17 upon challenge with OVA that in turn leads to airway neutrophilia and airway hyperresponsiveness (AHR). Ongoing Th17 responses to inhaled allergens might therefore distinguish severe asthma from less serious Th2-mediated diseases of the airway. In addition to studying the mechanisms underlying the induction and actions of Th2 and Th17 cells in the lung, we also study the impact of various environmental agents on pulmonary dendritic cell activation, and how these agents can act as adjuvants in the lung to promote allergic sensitization through the airway. For example, we have found that the bacterial product, flagellin, primes very strong allergic responses to the experimental allergen, OVA, as well as to natural allergens present in common house dust. Efforts to understand the mechanism by which flagelling promotes allergic sensitization are currently underway. There are two major populations of resident lung dendritic cells. One population displays the cell surface molecule, CD103, whereas the other subset displays a different marker, CD11b. The latter can be divided into three distinct subsets by flow cytometery. We are comparing the functions of these four dendritic cell subsets following their enrichment by flow cytometry-based sorting and culture with antigen-specific, naive T cells. Together, these approaches should allow us to identify and characterize cellular and molecular mechanisms that lead to allergic sensitization to inhaled allergens.

Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
2013
Total Cost
$1,611,022
Indirect Cost
City
State
Country
Zip Code
McAlees, J W; Whitehead, G S; Harley, I T W et al. (2015) Distinct Tlr4-expressing cell compartments control neutrophilic and eosinophilic airway inflammation. Mucosal Immunol 8:863-73
Nakano, Hideki; Moran, Timothy P; Nakano, Keiko et al. (2015) Complement receptor C5aR1/CD88 and dipeptidyl peptidase-4/CD26 define distinct hematopoietic lineages of dendritic cells. J Immunol 194:3808-19
Moran, Timothy P; Nakano, Keiko; Whitehead, Gregory S et al. (2015) Inhaled house dust programs pulmonary dendritic cells to promote type 2 T-cell responses by an indirect mechanism. Am J Physiol Lung Cell Mol Physiol 309:L1208-18
Whitehead, Gregory S; Thomas, Seddon Y; Cook, Donald N (2014) Modulation of distinct asthmatic phenotypes in mice by dose-dependent inhalation of microbial products. Environ Health Perspect 122:34-42
Moran, Timothy P; Nakano, Hideki; Kondilis-Mangum, Hrisavgi D et al. (2014) Epigenetic control of Ccr7 expression in distinct lineages of lung dendritic cells. J Immunol 193:4904-13
Coghill, James M; Fowler, Kenneth A; West, Michelle L et al. (2013) CC chemokine receptor 8 potentiates donor Treg survival and is critical for the prevention of murine graft-versus-host disease. Blood 122:825-36
Nakano, Hideki; Cook, Donald N (2013) Pulmonary antigen presenting cells: isolation, purification, and culture. Methods Mol Biol 1032:19-29
Nakano, H; Free, M E; Whitehead, G S et al. (2012) Pulmonary CD103(+) dendritic cells prime Th2 responses to inhaled allergens. Mucosal Immunol 5:53-65
Draper, David W; Gowdy, Kymberly M; Madenspacher, Jennifer H et al. (2012) ATP binding cassette transporter G1 deletion induces IL-17-dependent dysregulation of pulmonary adaptive immunity. J Immunol 188:5327-36
Yang, Xuebin; Walton, William; Cook, Donald N et al. (2011) The chemokine, CCL3, and its receptor, CCR1, mediate thoracic radiation-induced pulmonary fibrosis. Am J Respir Cell Mol Biol 45:127-35

Showing the most recent 10 out of 15 publications