Allergic asthma is a chronic inflammatory disease in which an inappropriate Th2 immune response plays a dominant role. Antigen presenting cells, particularly lung dendritic cells (DCs), are essential for the initiation and expression of pulmonary immunity by T cells. The capacity of DCs to stimulate T cells to become Th1 or Th2 cells in a primary immune response is strongly influenced by other cells and their secreted products in the immediate vicinity, i.e., microenvironment, of the DCs. Respiratory pathogens have been associated with either an increased or decreased risk for the development of asthma. We speculate that this altered asthma risk may relate to the capacity of the infectious agent to create a lung microenvironment that influences DCs to mature into either Th1 promoting or Th2 promoting DCs. Furthermore, once Th2 mediated lung inflammation is established, we speculate DC numbers increase and DC function is enhanced to perpetuate the response. We propose three aims to address the role of lung DCs in the primary and secondary immune responses of allergic asthma using both murine models and samples from people with asthma.
Aim 1 will test the hypothesis that active pulmonary inflammation at the time of initial exposure to allergen influences lung DCs to mature to either Th1-promoting (type 1) or Th2-promoting (type 2) DCs.
In Aim 2, we will test the hypothesis that lung DCs isolated from lungs undergoing allergic inflammation are influenced by their microenvironment to become the most potent resident antigen presenting cells for re-stimulating specific Th2 cells. To accomplish this aim, we will compare lung DCs, macrophages, B cells and IgE-armed mast cells in stimulating clonal Th2 cells to produce enhanced allergic inflammation and airway hyperreactivity.
In aim 3, we will test the hypothesis that Th2 mediated inflammation in the lungs of asthmatic individuals induces the recruitment, maturation and commitment of peripheral blood monocytes into DCs with the capacity to initiate and elicit potent Th2 responses. We will use three approaches to test this hypothesis, one using murine bone marrow-derived cells inoculated into mice with allergic inflammation, one assessing the effect of bronchoalveolar lavage fluids from asthmatics on human peripheral blood monocytes and monocyte-derived DCs, and one enumerating immature and mature lung DCs in bronchial biopsies from asthmatics and controls and also asthmatics before and after anti IgE therapy. The overall goal is to understand how lung DCs regulate lung immunity to cause asthma, with the hope of devising strategies to prevent and treat chronic immune-mediated pulmonary inflammation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
5P50HL056384-09
Application #
7006087
Study Section
Project Start
Project End
Budget Start
2004-12-01
Budget End
2005-11-30
Support Year
9
Fiscal Year
2005
Total Cost
$254,756
Indirect Cost
Name
University of New Mexico
Department
Type
DUNS #
868853094
City
Albuquerque
State
NM
Country
United States
Zip Code
87131
Chand, Hitendra S; Montano, Gilbert; Huang, Xuesong et al. (2014) A genetic variant of p53 restricts the mucous secretory phenotype by regulating SPDEF and Bcl-2 expression. Nat Commun 5:5567
Chand, Hitendra S; Schuyler, Mark; Joste, Nancy et al. (2010) Anti-IgE therapy results in decreased myeloid dendritic cells in asthmatic airways. J Allergy Clin Immunol 125:1157-1158.e5
Oliver, Janet M; Tarleton, Christy A; Gilmartin, Laura et al. (2010) Reduced FcepsilonRI-mediated release of asthma-promoting cytokines and chemokines from human basophils during omalizumab therapy. Int Arch Allergy Immunol 151:275-84
Chigaev, Alexandre; Waller, Anna; Amit, Or et al. (2009) Real-time analysis of conformation-sensitive antibody binding provides new insights into integrin conformational regulation. J Biol Chem 284:14337-46
Hahn, Andrew C; Lyons, C Rick; Lipscomb, Mary F (2008) Effect of Bacillus anthracis virulence factors on human dendritic cell activation. Hum Immunol 69:552-61
Chigaev, Alexandre; Waller, Anna; Amit, Or et al. (2008) Galphas-coupled receptor signaling actively down-regulates alpha4beta1-integrin affinity: a possible mechanism for cell de-adhesion. BMC Immunol 9:26
Gilmartin, Laura; Tarleton, Christy A; Schuyler, Mark et al. (2008) A comparison of inflammatory mediators released by basophils of asthmatic and control subjects in response to high-affinity IgE receptor aggregation. Int Arch Allergy Immunol 145:182-92
Chigaev, Alexandre; Waller, Anna; Zwartz, Gordon J et al. (2007) Regulation of cell adhesion by affinity and conformational unbending of alpha4beta1 integrin. J Immunol 178:6828-39
Hernandez-Hansen, Valerie; Bard, Julie D J; Tarleton, Christy A et al. (2005) Increased expression of genes linked to FcepsilonRI Signaling and to cytokine and chemokine production in Lyn-deficient mast cells. J Immunol 175:7880-8
Larson, Richard S; Davis, Terry; Bologa, Cristian et al. (2005) Dissociation of I domain and global conformational changes in LFA-1: refinement of small molecule-I domain structure-activity relationships. Biochemistry 44:4322-31

Showing the most recent 10 out of 47 publications