In urban settings, allergic asthma is often associated with a Th2 polarized T cell response to """"""""harmless"""""""" allergens. However, despite sensitization and exposure to allergens, only a subset of individuals expresses respiratory manifestations of allergy and respiratory manifestations are variable within an individual. These clinical characteristics of asthma suggest the importance of localized immune responses that control respiratory expression of allergy and suggest that respiratory expression of allergy may be associated with a perturbation in a local suppressive milieu. In the urban environment, inhaled particulate matter (PM) including diesel exhaust particles (DEP) may serve to disrupt immune responses. Bronchial epithelial cells (BECs), the first targets for ambient PM, release a myriad of cytokines in response to exposure. In the airway, dendritic cells (DC) are adjacent to BECs and transit rapidly to regional lymph nodes. As such, the microenvironment provided by BECs has the potential to influence DC. Immune responses are regulated by DCs that have the ability to evoke localized T cell responses including mucosal tolerance or polarized T cell responses. The close association between BECs and DC suggests that the microenvironment provided by BECs has the potential to influence DC subset trafficking, maturation and polarization, and thus subsequent T cell responses. This proposal will focus on the epithelial cell-DC interface and will address the overall hypothesis that DEP stimulation of bronchial epithelial cells results in the loss of normal DC-derived T cell tolerance and promotes DC mediated Th2 responses to common allergens. We will address the hypothesis with three specific aims 1) To test the hypothesis that DEP treatment of human BECs induces selective recruitment of myeloid DC as opposed to plasmacytoid DC using monocyte-derived DC, blood-derived DC and lung-derived DC;2) To test the hypothesis that DEP treatment of HBECs induces effector DC maturation and polarization with a loss of tolerizing DC with a focus on regulation of epithelial cell-derived GM-CSF, TSLP, IL-10, and TGF-beta using FACs analysis, quantitative RT-PCR, and siRNA and 3) To test the hypothesis that inhalation of DEP disrupts mucosal tolerance to harmless allergens using in vivo murine models of ovalbumin and cockroach tolerance and sensitization. These studies will provide biologic plausibility to explain the increase in allergic asthma associated with pollution exposures.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES010187-10
Application #
8048068
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Nadadur, Srikanth
Project Start
1999-12-01
Project End
2012-02-28
Budget Start
2011-06-01
Budget End
2012-02-28
Support Year
10
Fiscal Year
2011
Total Cost
$345,960
Indirect Cost
Name
New York University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
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