Studies in this proposal will utilize cutaneous allergen challenge to determine the basis for the observed efficacy of glucocorticoids (GC) in the treatment of allergic diseases. Previous studies have shown that both systemic and topical GC inhibit the cellular influx as well as the clinical parameters of the reaction seen 3 - 12 hours after allergen challenge, the so-called late phase reaction (LPR). Cellular recruitment is a highly regulated process that requires the coordination of endothelial adhesion molecules (EAM) and their counterreceptors on circulating leukocytes along with local production of chemotactic cytokines. In vitro models have shown that GC are capable of inhibiting cytokine production in various cell lines even after stimulation. Studies outlined in this proposal will test the hypothesis that GC inhibit the expression of endothelial adhesion molecules by inhibiting the production of the known endothelial-activating cytokines (IL-1, TNF, IL-4, and interferon-gamma. Additional studies in this proposal will focus on the regulation of a newly-identified chemokine called RANTES, which has been shown to be a potent chemoattractant for eosinophils and memory lymphocytes, two cell types that are selectively recruited in the LPR. To test these hypotheses we will employ routine histology, immunohistochemistry, and in situ hybridization methodologies using biopsies of allergic subjects following experimental allergen challenge. In addition, biopsy samples will be processed for analysis of cytokine mRNA by RNase protection assays and ELISAs for detection of RANTES and soluble adhesion molecule. Information provided by this work may help us to better understand the mechanisms by which GC alleviate allergic diseases as well as other inflammatory conditions such as connective tissue diseases, vasculitides, inflammatory dermatoses, etc. A better understanding of how GC provides benefit in the treatment of such disorders may eventually lead to the engineering of an anti-inflammatory medication which has the efficacy of GC with reduced side effects.
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| Matsumoto, K; Appiah-Pippim, J; Schleimer, R P et al. (1998) CD44 and CD69 represent different types of cell-surface activation markers for human eosinophils. Am J Respir Cell Mol Biol 18:860-6 |
| Beck, L A; Dalke, S; Leiferman, K M et al. (1997) Cutaneous injection of RANTES causes eosinophil recruitment: comparison of nonallergic and allergic human subjects. J Immunol 159:2962-72 |
| Beck, L A; Stellato, C; Beall, L D et al. (1996) Detection of the chemokine RANTES and endothelial adhesion molecules in nasal polyps. J Allergy Clin Immunol 98:766-80 |
