STEROID MECHANISMS IN CUTANEOUS ALLERGIC INFLAMMATION

这项提案中的研究将利用皮肤过敏原挑战 确定糖皮质激素(GC)观察疗效的依据 过敏性疾病的治疗。此前的研究表明，两者都 全身性和外部性GC抑制细胞内流以及临床 变应原攻击后3-12小时的反应参数， 所谓的后期反应(LPR)。细胞招募是一种高度 需要协调内皮细胞黏附的调节过程 循环白细胞上的EAM分子及其受体 局部产生趋化细胞因子。体外模型显示 GC能够抑制各种细胞系中细胞因子的产生 即使在刺激之后。这项提案中概述的研究将测试 GC抑制内皮细胞黏附分子表达的假说 通过抑制已知的内皮激活细胞因子的产生 IL-1、肿瘤坏死因子、IL-4和干扰素-γ。本提案中的其他研究 将专注于对一种名为RANTES的新发现的趋化因子的调控， 它已被证明是一种对嗜酸性粒细胞和 记忆淋巴细胞，两种细胞类型，选择性地在 LPR。为了验证这些假设，我们将采用常规的组织学方法， 免疫组织化学和原位杂交方法 实验性过敏原激发后过敏受试者的活组织检查。在……里面 此外，活检样本将通过以下方式进行细胞因子mRNA的分析 核糖核酸酶保护试验和酶联免疫吸附试验检测RANTES和可溶性 黏附分子。 这项工作提供的信息可能有助于我们更好地理解 GC减轻过敏性疾病及其他疾病的机制 炎症性疾病，如结缔组织病、血管炎、 炎症性皮肤病等。更好地理解GC如何提供 在治疗这类疾病方面的好处可能最终导致 一种具有GC疗效的抗炎药物的工程设计 副作用减少。

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.