CONSEQUENCES OF THYMIC ATROPHY INDUCED BY TCDD AND E2

雌激素和二恶英都有很强的免疫调节作用。 他们 都诱导免疫抑制和胸腺萎缩。 雌激素也 与人类的某些自身免疫性疾病明显相关， 啮齿类动物，而二恶英暴露已被证明会诱导某些标志物， 高度免疫 萎缩诱导和减少的动力学 与这种萎缩相关的淋巴细胞干细胞靶点是显著的， 这些试剂在环境或生物学上的相似性 相关剂量。 与皮质类固醇不同，单剂量的2，3，7，8- 四氯二苯并对二恶英（TCDD）或戊酸雌二醇（E2） 老鼠引起的萎缩需要几天才能显现出来， 持续数周，似乎与非胸腺干细胞有关 细胞减少。 这两种媒介都通过 它们的特异性受体，芳香烃受体（AhR）或雌激素 受体（ER），其是参与调节 在大多数细胞类型中的基因表达。 E2和TCDD不仅会导致 胸腺萎缩，但也不像皮质类固醇或辐射，诱导 肝淋巴细胞数量增加，许多表达T细胞受体 通常在选定的小鼠品系的外周中缺失。 长 范围目标是确定这些受体的激活如何 导致胸腺萎缩和T细胞的出现， 自身免疫性疾病 这些受体的抑制剂（部分或 完全拮抗剂）延迟或逆转正常年龄相关的胸腺萎缩？ 这种抑制剂能预防或延缓自身免疫性疾病吗？ 具体而言，将对胸腺的机制进行研究， 通过确定细胞类型， 在胸腺和胸腺干细胞中表达这些受体 隔间 在确定为萎缩关键的时间点 诱导或恢复，受体的激活状态将是 由它们与特定DNA反应结合的能力决定 元件，i被认为是近端细胞的候选者的细胞类型。 目标的 特定抗雌激素（如ICI） 164，384）和部分TCDD拮抗剂（例如，α-萘酮）可以 将确定这些药物是否能预防萎缩诱导。 的 在正常生理老化过程中受体的活性，以及是否 抑制剂可以延缓或逆转正常的年龄相关的萎缩， 被确定。 这两种药物诱导的肝淋巴细胞数量增加， 试剂将是表型，包括确定，通过使用干细胞 重组激活基因（RAG-1和2）和末端标记 转移酶（TdT）是否在肝脏中从头产生， 细胞，或者他们是否是移民。 所描述的抑制剂是否 以上，作为可以防止胸腺萎缩的剂量，可以防止 将检查这些肝淋巴细胞的外观。 研究将扩大对自身免疫性疾病的潜力 成人自身免疫性疾病中E2和TCDD的产生或加速 模型（SWR x NZB，SLE模型）。 B6 x AJ小鼠围产期暴露模型 新生儿出生3天后发生器官特异性自身免疫性疾病 还将检查胸腺切除术。

Both estrogens and dioxins have potent immunomodulatory properties. They both induce immunosuppression and thymic atrophy. Estrogens have also been clearly associated with certain autoimmune diseases in humans and rodents, while dioxin exposure has been shown to induce certain markers of hyperimmunity. The kinetics of atrophy induction and reductions in lymphocyte stem cell targets associated with this atrophy are remarkably similar between these agents at pharmacologically or environmentally relevant doses. Unlike corticosteroid, single doses of 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD) or 17beta-estradiol valerate (E2) in mice cause an atrophy that takes several days to manifest itself but persists for several weeks, and appears to be related to nonthymic stem cell reductions. Both of these agents mediate their affects through their specific receptors, the aryl hydrocarbon receptor (AhR) or estrogen receptor (ER) which are transcription factors involved in modulation of gene expression in most cell types. Both E2, and TCDD not only cause thymic atrophy, but also, unlike corticosteroid or radiation, induced increased numbers of liver lymphocytes, many expressing T-cell receptors normally deleted in the periphery of selected mouse strains. The long range objectives are to determine how activation of these receptors can lead to thymic atrophy and the appearance of T-cells that could promote autoimmune disease. Will inhibitors of these receptors (partial or complete antagonists) delay or reverse normal age related thymic atrophy? Will such inhibitors prevent or delay autoimmune disease? Specifically, studies will be carried out on the mechanism of thymic atrophy induction by these agents by determining the cell types expressing these receptors in the thymus and thymic stem cell compartments. At time points determine to be critical to atrophy induction or recovery, the activation status of the receptors will be determined by their ability to bind to their specific DNA response elements, i the cell types believed to be candidates for proximal targets. The dosimetry at which specific anti-estrogens (such as ICI 164,384), and partial TCDD antagonists (e.g., a-napthoflavone) can prevent atrophy induction by these agents will be determined. The activity of the receptors during normal physiological aging, and whether the inhibitors can delay or reverse normal age related atrophy will also be determined. The increased populations of liver lymphocytes induced by these two agents will be phenotype, including determining, by use of the stem cell markers for the recombination activating genes (RAG-1 and 2) and terminal transferase (TdT) whether they arise de novo in the liver from stem cells, or whether they are migrants. Whether the inhibitors described above, as doses that can prevent thymic atrophy, can prevent the appearance of these liver lymphocytes will be examined. Studies will be extended on the potential for autoimmune disease production or acceleration by both E2 and TCDD in an adult autoimmune model (SWR x NZB, SLE model). A perinatal exposure model in B6 x AJ mice which develop organ specific autoimmune disease after 3 days old neonatal thymectomy will also be examined.