Asthma is a chronic inflammatory disease. T lymphocytes are essential for initiating and maintaining the asthmatic inflammatory immune response. Corticosteroid treatment targets several inflammatory responses, including T lymphocytemediated responses. In addition, leukotriene receptor antagonists (LTRA) may influence T cell activation. To investigate the effects of these two controller agents in the treatment of asthma on airway function is the goal of the IMPACT clinical trial mild chronic adult asthmatics. In this proposal we will examine the cellular and molecular mechanisms of corticosteroid and an LT-RA, focusing on their effects on T lymphocytes during both chronic (18 months) and acute therapy. Complete T cell activation during allergen exposure requires antigen signals mediated by the T cell receptor plus costimulatory signals. The best- characterized costimulatory pathway involves the receptors CD28, CTLA4 and ICOS expressed on T lymphocytes and the ligands CD80, CD86 and B7-h expressed primarily on antigen presenting cells. While CD28 is expressed constitutively on most T lymphocytes, CTLA4, ICOS, CD80, CD86 and B7-h are upregulated during an immune response and are the focus of this proposal. We have previously demonstrated that pulmonary inflammation and airway hyperresponsiveness is dependent upon T cell costimulation in a model of allergic asthma. We postulate that the T lymphocyte costimulatory pathway is a critical target for effective asthma therapy. Specifically, our hypothesis proposes that the function of the costimulatory receptors CTLA4 and ICOS and their ligands CD80, CD86 and B7h, will be downregulated after treatment with corticosteroids and/or a leukotriene receptor antagonist (LT-RA) in mild persistent asthmatics. Analyzing samples before and after asthma therapy, Aim 1 will determine the mechanisms by which the costimulatory receptors, CTLA4 and ICOS, are regulated.
Aim 2 will investigate changes in the immunoregulation of costimulatory ligands, CD80, CD86 and B7-h.
Aim 3 will identify differentially expressed T lymphocyte genes using expression array analysis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL067684-03
Application #
6607572
Study Section
Special Emphasis Panel (ZHL1-CSR-A (F4))
Program Officer
Noel, Patricia
Project Start
2001-04-01
Project End
2005-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
3
Fiscal Year
2003
Total Cost
$381,375
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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