2007 Progress Report: Dendritic Cell Activation by Particulate Matter and AllergenEPA Grant Number: R832139C004
Subproject: this is subproject number 004 , established and managed by the Center Director under grant R832139
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
Center: Johns Hopkins Center for Childhood Asthma in the Urban Environment
Center Director: Breysse, Patrick N.
Title: Dendritic Cell Activation by Particulate Matter and Allergen
Investigators: Georas, Steven
Institution: The Johns Hopkins University
EPA Project Officer: Callan, Richard
Project Period: November 1, 2003 through October 31, 2008 (Extended to October 31, 2010)
Project Period Covered by this Report: November 1, 2006 through October 31, 2007
RFA: Centers for Children's Environmental Health and Disease Prevention Research (2003) RFA Text | Recipients Lists
Research Category: Children's Health , Health Effects , Health
The overall goal of the proposal is to examine the influence of airborne particulates and bioaerosols on airway immune responses associated with asthma. The specific aims were: 1) to investigate the mechanisms by which Ambient Particulate Matter (APM) modulates the surface phenotype of myeloid dendritic cells differentiated in vitro to an activated state by LPS and 2) to investigate the mechanism by which APM modulates important immunologic functions of dendritic cells critical to host and protective immunity.
In the preceding funding period, Drs. Georas and Williams have continued their investigation into mechanisms of how airborne particulate matter (PM) affects dendritic cell (DC) maturation using different in vitro models of human and mouse DC. These studies have continued since their relocation to the University of Rochester Medical Center (URMC) in Rochester, NY in July of 2006. Using DC derived from anonymous human donors, we found that ambient PM from Baltimore induced a unique phenotype of DC activation characterized by modest reduction in endocytosis, upregulation of costimulatory molecule expression, enhanced cytokine gene expression, and augmented ability to activate T cells in co-culture. Importantly, using both allogeneic CD4+ cells in bulk as well as purified naïve CD45RA+ cells, we found that PM exposed DC enhanced the secretion of more IL-13 than IFN-gamma from T cells, indicative of a “Th2-like” phenotype. In addition, we found that expression of the surface receptors toll-like receptor (TLR) 2 and 4 were significantly reduced after exposure to PM. These data were recently published (Williams et al., 2007a). In a separate study, Dr. Williams investigated the effects of PM collected from the Baltimore Harbor tunnel on human DC and found an interesting pattern of differential gene expression depending on whether the samples were enriched in car or truck exhaust with the latter being more active in general: this manuscript was recently published (Porter at al., 2007).
In recent studies, we have been investigating the signal transduction pathways by which PM activates DC using human and mouse models. With human monocyte derived DC, we are investigating the activation of different signaling cascades including the mitogen activated protein kinases (MAPK) and NOD proteins. These experiments are being conducted in parallel with studies using MAPK inhibitors to antagonize the functional effects of PM on DC activation. In collaboration with Dr. Maureen Horton, we used gene-targeted mice deficient in TLR2, TLR4 and the TLR2/4 adaptor protein Myd88 to study what aspects of DC activation were attenuated using bone marrow-derived DC (BM-DC). These studies revealed that different aspects of DC activation were attenuated in a TLR/Myd88 independent manner and are contained in part in the on-line supplement to Williams et al., 2007a. We have also used microarray technology to investigate the patterns of genes altered by PM in dendritic cells, monocytes and alveolar macrophages. These data are contained in part in Williams et al., 2007b, and revealed several novel findings including a broadly dysregulated pattern of gene expression in PM-stimulated DC including numerous chemokines, cytokines and adaptor molecules.
Dr. Williams and Dr. Georas plans during the next year are to examine the effects of indoor particulates collected form smoking and non smoking homes for their ability to active human monocyte-derived DC. As time allows responses will be compared in cells collected from atopic donors to examine the effect of co- stimulation with allergens.
Journal Articles on this Report : 2 Displayed | Download in RIS Format
|Other subproject views:||All 7 publications||7 publications in selected types||All 7 journal articles|
|Other center views:||All 113 publications||113 publications in selected types||All 110 journal articles|
||Williams MA, Porter M, Roman J, Breysse P, Williams D, Georas SN. Ambient Baltimore Particulate Matter Directs Non-Classical Immune Activation of Human Myeloid Dendritic Cells. Journal of Allergy and Clinical Immunology 2007;119(2):488-497.||
||Williams MA, Cheadle C, Watkins T, Killedar S, Tailor A, Barnes K, Georas S. TLR2 and TLR4 are potential biomarkers of environmental particulate matter exposed human myeloid dendritic cells. Biomarker Insights 2007;2:225-239.||
Supplemental Keywords:RFA, Health, Scientific Discipline, PHYSICAL ASPECTS, Air, HUMAN HEALTH, particulate matter, Health Risk Assessment, Genetics, Allergens/Asthma, Health Effects, Physical Processes, asthma, children's health, asthma triggers, air toxics, exposure, air pollution, children, bioaerosols, air pollutant, human exposure, airborne pollutants, PM, allergens
Progress and Final Reports:Original Abstract
Main Center Abstract and Reports:R832139 Johns Hopkins Center for Childhood Asthma in the Urban Environment
Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R832139C001 The Epidemiology of Susceptibility to Airborne Particulates and Allergens to Asthma in African Americans
R832139C002 A Randomized Controlled Trial of Behavior Changes in Home Exposure Control
R832139C003 Mechanisms of Particulate-Induced Allergic Asthma
R832139C004 Dendritic Cell Activation by Particulate Matter and Allergen