The central hypothesis for this SCOR proposal is that the initial event in allergic asthma is an inappropriately regulated (dysregulated) pulmonary immune response to an inhaled antigen, which is dependent on a combination of genetics, the developmental stage of the immune response, environmental effects, and the local cytokine milieu at the time of initial allergen challenge. This dysregulated immune response results in the local accumulation of allergen-specific IL-4 and IL-5 secreting T cells (a Th2 response). IL-4 and IL-5 enhance the development of specific IgE antibodies and eosinophilia, respectfully, followed by bronchial inflammation with increased local eosinophils, mast cells, and basophils; bronchial hyperresponsiveness; and the clinical expression of asthma. This proposal consists of five projects, which will examine different aspects of immune regulation and inflammation in asthma. Each project is a direct extension of ongoing research by principal investigators who are seasoned senior scientists. Project 1(Lipscomb) will examine what regulates T cell subset development and traffic to lungs in an OVA T cell receptor transgenic mouse model, the relative importance of IgE and eosoinphils on bronchial inflammation in a nontransgenic mouse model, and the effects of steroids and cromolyn on modifying pulmonary immunity and inflammation in both models. Project 2 (Oliver) will dissect intracellular signaling pathways in human mast cells and basophils and examine the hypothesis that intrapulmonary allergen exposure in asthmatics alters peripheral blood basophil signaling and adhesive properties. Project 3 (Schuyler), the clinical project, will determine whether the local lung environment in asthmatics influences the response to new aeroantigens. This project also proposes to determine whether suppressing local inflammation may alter an immune response to either locally instilled or systemically administered neoantigens. An Immunology Core laboratory (Lewis) will centralize most of the large numbers of immunologic assays required for the proposed studies. Collectively, these studies should provide important information about the cellular and molecular mechanisms of asthma and suggest possible new interventions in treating the disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
5P50HL056384-02
Application #
2716490
Study Section
Special Emphasis Panel (ZHL1-CSR-Q (M1))
Project Start
1996-12-01
Project End
2001-11-30
Budget Start
1997-12-01
Budget End
1998-11-30
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of New Mexico
Department
Pathology
Type
Schools of Medicine
DUNS #
829868723
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

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