Mechanism for maternal transfer of asthma risk

描述(由申请人提供)：哮喘是一个重要的世界性健康问题。其病因与Th1/Th2轴向Th2倾斜有关。GMCSF和IL-4和IL-13使这个轴偏向Th2。树突状细胞(DC)在哮喘中也起着重要作用。它们是强大的抗原提呈细胞，能够激发原始T细胞。根据微环境和共刺激物的不同，DC可以使Th1/Th2轴在任一方向上极化。一些研究也表明哮喘肺中的DC具有异常的功能。流行病学研究表明，子代的哮喘风险优先通过母体传播。其机制尚不清楚，但可能与宫内环境有关。我们推测，GMCSF和IL-4/13通过胎盘途径改变了胚胎树突状细胞的表型，增加了后代对哮喘的易感性。使用小鼠模型，这一假设将分三个阶段进行检验。首先，我们将利用细胞因子受体基因敲除小鼠来确定GMCSF和IL-4/13是否穿过胎盘。其次，将通过T细胞增殖研究比较患有哮喘母亲和非哮喘母亲的后代的DC特征。第三，将使用基因阵列比较这两组树突状细胞的基因表达模式

DESCRIPTION (provided by applicant): Asthma is a significant worldwide health issue. Its etiology is related to the skewing of the Th1/Th2 axis toward Th2. GMCSF and interleukins (IL) 4 and 13 polarize this axis toward Th2. Dendritic cells (DC's) also play a prominent role in asthma. They are potent antigen presenting cells and are uniquely able to prime naive T- cells. Depending on the microenvironment and co-stimulators, DC's can polarize the Th1/Th2 axis in either direction. Some studies also indicate that DC's in asthmatic lungs have aberrant function. Epidemiologic studies have shown that asthma risk in offspring is preferentially transferred maternally. The mechanism is unknown, but may be related to in utero milieu. We postulate that the transplacental passage of GMCSF and IL-4 /13 alters the phenotype of embryonic dendritic cells increasing susceptibility to asthma in offspring. Using a mouse model, this hypothesis will be tested in 3 stages. First, we will determine if GMCSF and IL- 4/13 cross the placenta using cytokine receptor knockout mice. Second, DC characteristics will be compared between the offspring of asthmatic mothers versus non-asthmatic mothers using T-cell proliferation studies. Third, dendritic cell gene expression patterns between these two groups will be compared using gene arrays