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2004 Progress Report: Dendritic Cell Activation by Particulate Matter and Allergen
EPA Grant Number: R832139C004Subproject: 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
Title: Dendritic Cell Activation by Particulate Matter and Allergen
Investigators: Georas, Steven
Institution: Johns Hopkins University
EPA Project Officer: Fields, Nigel
Project Period: November 1, 2003 through October 31, 2008 (Extended to October 31, 2010)
Project Period Covered by this Report: November 1, 2003 through October 31, 2004
RFA: Centers for Children's Environmental Health and Disease Prevention Research (2003)
Research Category: Children's Health , Health Effects
Description:
Objective:The overall goal of the research project is to examine the influence of airborne particulates and bioaerosols on airway immune responses associated with asthma. The specific objectives are to: (1) test the hypothesis that particulate matter (PM) influences dendritic cell (DC) maturation; and (2) test the hypothesis that PM interacts with allergen to induce a Th2-promoting DC phenotype.
Progress Summary:In ongoing studies, Dr. Georas found that lysophatidic acid (LPA) enhances IL-13 gene expression in submaximally activated T cells and does so in part at the level of transcriptional activation. More recently, he studied LPA effects on DC maturation because he had detected mRNA for LPA 1 and for LPA 2 in DC isolated from bronchoalveolar lavage fluids following segmental allergen challenge. His model of DC maturation uses CD 14+ myeloid cells differentiated for 5 days in the presence of granulocyte macrophage colony stimulating factor plus IL-4 to induce an immature phenotype (iDC) followed by 48-hour incubation with lipopolysaccharide (LPS) to induce mature DC (mDC). LPS as the maturation signal led to the expected increases in IL-12 and IL-10 secretion and surface expression of major histocompatibility complex (MHC) II and CD83. The addition of LPA to LPS strikingly inhibited the secretion of IL-12 and augmented IL-10 secretion. Given the key role of IL-12 in driving the Th1 response and the ability of IL-10 to augment IL-4 gene expression these data suggest that LPA-exposed DC will favor Th2 DC differentiation.
Preliminary Data Evaluation
In preliminary studies, Dr. Georas found that coculture of iDC with ambient PM collected from urban Baltimore induced typical mDC morphology, including cell flattening, enlargement, and cytoplasmic protrusions after culture for 48 hours. PM alone enhanced surface expression of human leukocyte antigen class II; CD 80 and PM also modulated LPS-induced DC maturation in a dose-dependent manner. These results provide important proof of principal that PM can affect the differentiation of myeloid DC in this model system.
Findings, Relevance to Field
Our findings have several implications to the field of asthma. First, to our knowledge these 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. DCs are the most potent antigen presenting cell in the lung. In peripheral tissues, immature DCs 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.
Future Activities:During Year 3 of the project, Dr. Georas plans to examine the effects of indoor particulates collected from smoking and nonsmoking homes for their ability to activate DC from anonymous white cell donors. As time allows, responses will be compared in cells collected from atopic donors to examine the effect of costimulation with allergens.
Journal Articles:No journal articles submitted with this report: View all 3 publications for this subproject
Supplemental Keywords:airborne particulates, asthma, dendritic cells, allergens, particulate matter, PM, children’s health,
,
HUMAN HEALTH, Air, Scientific Discipline, Health, RFA, PHYSICAL ASPECTS, Health Effects, Health Risk Assessment, Physical Processes, particulate matter, Allergens/Asthma, Genetics, allergens, children's health, air toxics, respiratory, air pollution, airborne pollutants, children, bioaerosols, exposure, asthma triggers, asthma, human exposure, PM
Progress and Final Reports:
Original Abstract
2005 Progress Report
2006 Progress Report
2007 Progress Report
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