2006 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, 2005 through October 31, 2006
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 was 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 DC. These models allow for the study of how PM affects the maturation of immature dendritic cells (iDC) cells when compared with the classic environmental stimulant lipopolysaccharide (LPS). The main result is that PM induces a distinct form of DC maturation that shares some features with LPS but also has a unique signature including striking downregulation of the pattern recognition receptors TLR 2 and TLR4 and the production of IL-10. In addition, the production of the Th2-polarizing cytokine IL-6, was markedly up-regulated following stimulation of iDC with PM. One of the most important observations made from these experiments is that PM-primed dendritic cells promote an increase in the expression of both IL13 and IFN-gamma (with an increase in the IL-13 to IFN-gamma ratio) in co-culture with CD4+ T cells. Thus, these studies firmly implicate PM as a novel agent acting on DC to promote pro-inflammatory Th2-like immune responses. Given that Th2 immune responses are a hallmark of allergic asthma, these studies open a new area of research into how environmental pollutants affect asthma immunology. These studies were presented at the 2006 American Thoracic Society Conference (oral session and abstract).
Our findings have several implications to the field of asthma. First, to our knowledge they are the first studies to demonstrate that ambient particulates can directly alter cells that are pivotal in the maturation and establishment of the immunologic state characteristic of asthma. Dendritic cells are the most potent antigen presenting cell in the lung. In peripheral tissues, immature DC and respond to innate immune signals such as LPS characterized by increased formation of MHC peptide complexes a higher expression of costimulatory molecules, altered expression of chemokine receptors that facilitate movement into lymphoid tissues and synthesis of chemokines and cytokines that influence T cell differentiation including IL-6, IL-10 and IL-12. Not only will this influence evolution to the characteristic “Th2 bias” in asthma but there is suggestive evidence in animal models that they are critical to altering airway responsiveness to lead to the characteristic asthma phenotype. The availability of an in vitro model to examine these processes is extremely valuable both for understanding basic pathways and for examining the basis of individual responses.
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 DC from anonymous cell donors. 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 : 1 Displayed | Download in RIS Format
|Other subproject views:||All 7 publications||7 publications in selected types||All 7 journal articles|
|Other center views:||All 114 publications||114 publications in selected types||All 111 journal articles|
||Williams MC, Georas S. Gene expression patterns and susceptibility to allergic responses. Expert Review of Clinical Immunology 2006;2(1):59-73.||
Supplemental Keywords:RFA, Health, Scientific Discipline, PHYSICAL ASPECTS, Air, HUMAN HEALTH, particulate matter, Genetics, Health Risk Assessment, Allergens/Asthma, Health Effects, Physical Processes, asthma, asthma triggers, children's health, air toxics, exposure, air pollution, children, airborne pollutants, human exposure, bioaerosols, air pollutant, 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