Estrogen-T cell Interactions

说明(申请人提供)：雌激素在健康和疾病中有广泛的应用。绝经后的妇女接受雌激素替代疗法治疗，以缓解绝经症状。1940-1975年间，估计有500万至1000万美国人在怀孕期间或在子宫中接触到己烯雌酚(DES)，这是一种合成雌激素。暴露于DES与“DES母亲”患乳腺癌的风险增加和“DES女儿”患子宫颈阴道癌的终生风险有关。暴露于DES还与“DES儿女”的一系列异常有关，包括免疫系统障碍，如自身免疫性疾病、癌症和某些感染的发生率增加。此外，已鉴定出许多异种雌激素，包括环境雌激素和植物雌激素，它们与雌激素受体(ER)结合，并介导类似生理雌激素的活性。因此，对DES的研究可以作为研究越来越多的内分泌干扰物的模板。本实验室的研究首次证实，出生前和出生后暴露于雌二醇(E2)和DES可诱导胸腺细胞凋亡，改变T细胞受体和CD分子的表达，调节T细胞的正负选择。在目前的研究中，我们将检验这一中心假设，即产前暴露于DES会改变胸腺中T细胞的阳性和/或阴性选择，导致对自身抗原的反应性增强和对非自身抗原的反应性降低的偏斜T细胞库的产生。在目标1中，我们将研究Fas和Fas配体基因的调控是否涉及雌激素反应元件(ERE)和其他转录因子。目的#2将测试产前暴露于DES是否改变胸腺T细胞的阳性和阴性选择，从而使成熟T细胞对自身抗原而不是非自身抗原的免疫反应性发生扭曲。目的#3探讨Era在DES诱导的细胞凋亡和自身免疫发展中的作用。此外，还将研究T细胞-基质细胞相互作用在DES诱导胸腺细胞凋亡中的作用。在目标4中，将测试产前接触DES导致出生后自身免疫性疾病易感性增加的机制。总之，建议的研究应该为产前暴露于DES导致出生后增加自身免疫和癌症易感性的机制提供新的信息，并为开发预防这种免疫毒性的潜在方法提供新的信息。 与公共卫生相关：在怀孕期间服用己烯雌酚的妇女以及她们的儿子和女儿中，癌症和自身免疫性疾病的发病率很高。绝经后的妇女在激素替代疗法中使用雌激素，以及在环境和食物中发现的几种化学物质作为雌激素，导致严重的健康问题。因此，我们的研究旨在为雌激素调节其对免疫系统的毒性效应的机制提供洞察力，从而导致制定预防和治疗策略。

DESCRIPTION (provided by applicant): Estrogens have widespread applications in health and disease. Postmenopausal women are treated with estrogen replacement therapy to relieve them of the menopausal symptoms. Between 1940-1975, an estimated 5-10 million Americans received diethylstilbestrol (DES), a synthetic estrogen, during pregnancy or were exposed to the drug in utero. Exposure to DES has been associated with an increased risk for breast cancer in "DES mothers" and a lifetime risk of cervicovaginal cancers in "DES daughters". Exposure to DES has also been linked to a wide range of abnormalities in "DES sons and daughters" including immune system disorders such as increased incidence of autoimmunity, cancer and certain infections. Furthermore, a number of xenoestrogens which include environmental estrogens and phytoestrogens have been identified which bind estrogen receptors (ERs) and mediate activity similar to physiological estrogens. Thus, research on DES may serve as a template to study a growing list of endocrine disruptors. Studies from our lab demonstrated for the first time that prenatal and postnatal exposure to estradiol (E2) and DES can induce apoptosis in thymocytes, alter the expression of T cell receptor and CD molecules, and modulate positive and negative selection of T cells. In the current study, we will test the central hypothesis that prenatal exposure to DES alters the positive and/or negative selection of T cells in the thymus leading to generation of skewed T cell repertoire with enhanced reactivity towards self antigens and decreased response against non-self antigens. In aim# 1, we will investigate whether the regulation of Fas and Fas ligand genes involves estrogen responsive elements (ERE) and other transcription factors. Aim# 2 will test if prenatal exposure to DES alters positive and negative selection of T cells in the thymus and thereby skewing the immune responsiveness of mature T cells to self rather than non-self antigens. Aim# 3 will investigate the role of ERa in DES induced apoptosis and development of autoimmunity. Also, the role of T cell-stromal cell interactions in DES-induced thymocyte apoptosis will be studied. In Aim# 4, the mechanism by which prenatal DES exposure leads to increased susceptibility to autoimmune disease postnatally will be tested. Together, the studies proposed should provide novel information on the mechanism by which prenatal exposure to DES leads postnatally to increased susceptibility to autoimmunity and cancer and to development of potential approaches to prevent such immunotoxicity. PUBLIC HEALTH RELEVANCE: There has been a high incidence of cancers as well as autoimmune diseases observed in women who were prescribed during pregnancy, a synthetic estrogen known as diethylstilbestrol, as well as in their sons and daughters. Postmenopausal women administered estrogens in hormone replacement therapy, as well as, several chemicals found in the environment and foods act as estrogens causing significant health problems. Thus, our studies are aimed at providing insights into the mechanism by which estrogens mediate their toxic effects on the immune system, thereby leading to the development of strategies for their prevention and treatment.