The long term objectives of this project are to understand and delineate the mechanisms underlying """"""""difficult-to-manage asthma"""""""", particularly the immunologic responses which distinguish """"""""steroid resistant"""""""" (SR) from """"""""steroid sensitive"""""""" (SS) asthma, and the role of T lymphocytes in this process.
Specific aim one will define the immunologic determinants of SR asthma by assessing the T cell receptor (TCR) Vb gene usage of airway T cells vs peripheral blood T cells in these two forms of asthma, prior to and after a course of prednisone. The DNA sequence of V-D-J segments (junctional region) of the expanded TCR b-chains in airway and peripheral blood T cells from SR, as compared to SS, asthmatics will also be delineated.
Specific aim 2 will characterize the oligoclonally expanded airway T cells in SR asthmatics by analyzing cytokines produced by Vb- specific T cells.
Specific aim 3 will determine the molecular basis for impaired steroid responsiveness in SR asthma. In these experiments, cell extracts of peripheral blood mononuclear cells (PBMC) and airway cells from SS vs SR asthmatics will be assessed for expression of GCRa vs GCRb, an endogenous inhibitor of GCR binding.
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