Mechanism for maternal transfer of asthma risk

描述（由申请人提供）：哮喘是一个重大的全球性健康问题。其病因与Th 1/Th 2轴向Th 2倾斜有关。GMCSF和白细胞介素（IL）4和13使该轴朝向Th 2。树突状细胞（DC）在哮喘中也起着重要作用。它们是有效的抗原呈递细胞并且独特地能够引发初始T细胞。取决于微环境和共刺激因子，DC可以在任一方向上调节Th 1/Th 2轴。一些研究还表明哮喘肺中的DC具有异常功能。流行病学研究表明，后代的哮喘风险优先传递给母亲。其机制尚不清楚，但可能与子宫内环境有关。我们推测GM-CSF和IL-4 /13的经胎盘传代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，将分3个阶段检验该假设。首先，我们将使用细胞因子受体敲除小鼠确定GMCSF和IL- 4/13是否穿过胎盘。第二，使用T细胞增殖研究比较哮喘母亲与非哮喘母亲的后代之间的DC特征。第三，将使用基因阵列比较这两组之间的树突状细胞基因表达模式

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