Cytokine Profiles In Asthma And Allergic Diseases

哮喘是一种呼吸道炎症性疾病。过敏原暴露后，携带IgE的细胞，如肥大细胞和嗜碱性粒细胞，首先被激活。后来，T淋巴细胞进入呼吸道，被变应原激活，并通过IL-4、IL-5和干扰素-γ等细胞因子的分泌在调节这种炎症反应中发挥关键作用。本项目旨在研究肥大细胞、嗜碱性粒细胞和T细胞亚群的细胞因子和介体分布，这些亚群可能与哮喘呼吸道炎症的发生有关。类胰蛋白酶是一种主要由肥大细胞产生的促炎性蛋白水解酶。我们检查了外周血，以确定其他细胞群是否也能够表达类胰蛋白酶。类胰蛋白酶在外周血白细胞中的表达仅限于嗜碱性粒细胞系。令人惊讶的是，嗜碱性粒细胞类胰蛋白酶的表达在不同个体之间的差异超过100倍，在高表达类胰蛋白酶的个体中与组织肥大细胞的表达相当。嗜碱性粒细胞类胰蛋白酶的表达与哮喘或哮喘严重程度无关。这些结果表明，类胰蛋白酶是一种额外的介质，嗜碱性粒细胞可能通过该介质促进过敏性炎症。当被IgE的过敏原交联激活时，嗜碱性粒细胞通过分泌组胺和IL-4等介质而发挥效应作用。为了检验嗜碱性粒细胞作为此类介体的非IgE依赖来源的潜在作用，我们检测了柴油废气颗粒物(DEP)对嗜碱性粒细胞的影响。DEP是空气污染的一种成分，在体内充当Th2极化佐剂。体外接触DEP后，嗜碱性粒细胞以非IgE依赖的方式产生IL-4并释放组胺。DEP与变应原激活无协同作用。研究中的过敏药物抗IgE/奥马珠单抗治疗后，嗜碱性粒细胞减少FceRI的表达。在一项临床试验中，我们通过跟踪FceRI的表达来检验这种减少的动力学和药效学。奥马珠单抗导致FceRI表达下降70%，在研究药物后14天达到最大值，并在单次给药后28天持续。

Asthma is an inflammatory disease of the airways. After allergen exposure, IgE bearing cells, such as mast cells and basophils, are first activated. Later, T lymphocytes enter the airways, are activated by allergen and play a key role in regulating this inflammatory response through the elaboration of cytokines such as IL-4, IL-5 and IFN-gamma. This project seeks to examine the cytokine and mediator profiles of mast cell, basophil and T cell subpopulations that may be involved in the generation of inflammation in asthmatic airways. Tryptase is a pro-inflammatory protease mediator produced principally by mast cells. We examined peripheral blood to determine if other cell populations might also be capable of tryptase expression. Tryptase expression in peripheral blood leukocytes was limited to the basophil lineage. Surprisingly, basophil tryptase expression varied by more than 100 fold between individuals and in the high tryptase expressing individuals was comparable to that of tissue mast cells. Basophil tryptase expression did not correlate with asthma or asthma severity. These results suggest that tryptase represents an additional mediator through which basophils may contribute to allergic inflammation. When activated by allergen cross-linking of IgE, basophils play an effector role by their secretion of mediators such as histamine and IL-4. To examine a potential role for basophils as a non-IgE dependent source of such mediators, we examined the effect of diesel exhaust particles (DEP) on basophils. DEP is a component of air pollution that acts as a Th2-polarizing adjuvant in vivo. After DEP exposure in vitro, basophils produced IL-4 and released histamine in a non-IgE dependent manner. DEP showed no synergy with allergen activation. Basophils decrease expression of FceRI upon treatment with the investigational allergy drug anti-IgE/omalizulab. We examined the kinetics and pharmacodynamics of this decrease by following FceRI expression during a clinical trial. Omalizumab caused a 70% decrease in FceRI expression that was maximal by 14 days after the study drug and was sustained 28 days after a single dose.