PRENATAL DIETHYLSTILBESTROL EXPOSURE--IMMUNE DEFECTS

对人类和动物的研究表明，产前暴露于一种 合成雌激素，己烯雌酚(DES)，增加 对肿瘤和畸形性异常的易感性 生殖组织。现在提出了更多的担忧，即女性 产前暴露于DES也容易患上自身免疫性疾病。 动物研究也证明了雌激素化合物具有显著的 对免疫系统的影响。例如，正常小鼠在出生时暴露于 雌激素使胸腺萎缩，发展自身免疫力。这些老鼠 T细胞有丝分裂原的增殖能力受损，这是一种“生命” “长”缺陷提示免疫印记。T细胞缺陷 DES诱导可能有助于增加对肿瘤的易感性， 自身免疫性或传染性疾病、肿瘤或感染。我们假设 胎儿暴露于DES(处于免疫系统的关键阶段) 发育)可能会扭曲T细胞的个体发育。这可能会导致个人 免疫系统受损。为了检验这一假设，我们将把重点放在 子代T细胞表型和功能的研究 妊娠小鼠注射DES。小鼠从胚胎到出生都要接受检查 衰老年龄决定免疫变化是否是暂时性的 或者是永久的。这项提案的目的是；目标一：划定 产前染毒DES小鼠胸腺内T细胞的个体发育。得克萨斯- 用单抗确定T细胞个体发育的敏感期 Flow对发育调节的表面标志物的抗体 细胞学。此外，还将检测胸腺细胞的凋亡率和 与细胞凋亡标志物基因Fas的表达相关。目标一：要 产前暴露的脾T细胞增殖缺陷的解剖 老鼠..。将分析T细胞的变化：脾的数量 CD3/Alphabeta TCR细胞，活化标记的表达，对 细胞因子(如IL-2、IL-12)、细胞内钙水平和对 共刺激信号。目的三：分析其意义和性质 DES诱导的T细胞缺陷通过确定：(I)增强的免疫球蛋白 雌激素中抗dsDNA和心磷脂(一种磷脂)的自身抗体 暴露的小鼠是脾或肝T细胞改变的结果 Th1/Th2亚群失衡。向以下转变 Th2，可以解释自身抗体表达增加或T细胞减少。 细胞免疫；(Iii)体内T细胞反应的变化 Th1诱导抗原(B.bortus)。预计这些研究 将提供有关胎儿发育危险的新信息 高雌激素的母体环境，即发生的可能性 T细胞的先天缺陷。

Studies in humans and animals have shown that prenatal-exposure to a synthetic estrogen hormone, diethylstilbestrol (DES), increases susceptibility to neoplastic and teratogenic abnormalities of reproductive tissues. Additional concerns have now been raised that women prenatally-exposed to DES are also susceptible to autoimmune diseases. Animal studies also document that estrogenic compounds have a marked effect on the immune system. For example, normal mice perinatally exposed to estrogen have atrophied thymus and develop autoimmunity. These mice have impaired ability to proliferate to T cell mitogens, which is a "life long" defect suggestive of immunologic imprinting. Defects of T cells induced by DES may contribute to increased susceptibility to neoplastic, autoimmune or infectious diseases, tumors or infection. We hypothesize that exposure of fetuses to DES (at a critical stage of immune system development) may skew the T cell ontogeny. This may result in individuals with an impaired immune system. To test this hypothesis, we will focus our studies on the phenotype and function of T cells from offspring of pregnant mice injected with DES. Mice will be examined from fetal to senescent age to determine whether immunological changes are transient or permanent. The aims of this proposal are; Aim I: To delineate the intrathymic T cell ontogeny in mice prenatally-exposed to DES. The DES- sensitive stage in T-cell ontogeny will be determined by using monoclonal antibodies to developmentally-regulated surface markers by flow cytometry. Further, apoptosis of thymocytes will be determined and correlated with expression of fas, an apoptotic marker gene. Aim Il: To dissect defects in splenic T cell proliferation in prenatal DES-exposed mice.. T cells will be analyzed for alterations in: numbers of splenic CD3+/alphaBeta TCR+ cells, expression of activation markers, response to cytokines (eg. IL-2, IL-12), intracellular Ca++ levels and response to co-stimulatory signals. Aim III: To analyze the significance and nature of DES-induced T cell defects by determining whether: (i) augmented IgG autoantibodies to dsDNA and cardiolipin (a phospholipid) in estrogen- exposed mice is a consequence of altered help from spleen or liver T cells; (ii) there is an imbalance of Th1 and Th2 subsets. A shift towards Th2, may explain increased expression of autoantibodies or diminished T- cell mediated immunity; (iii) alterations in T cell response in vivo to Th1-inducer antigens (B.abortus). It is anticipated that these studies will provide new information on the hazards of development of fetuses in a hyperestrogenic maternal environment, i.e., potential for the genesis of birth defects of T cells.