CONSEQUENCES OF THYMIC ATROPHY INDUCED BY TCDD AND E2

TCDD 和 E2 引起的胸腺萎缩的后果

• 批准号: 2156422
• 负责人: ALLEN Edgar SILVERSTONE
• 金额: $ 21.51万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-07-01 至 1997-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2156422
• 关键词: aging; apoptosis; atrophy; autoimmune disorder; bone marrow; cytokine; dioxins; disease /disorder model; estradiol; estrogen receptors; gene expression; genetic strain; hematopoietic stem cells; laboratory mouse; lymphocyte; monoclonal antibody; perinatal; thymus disorder

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.

雌激素和二恶英都具有有效的免疫调节特性。 他们 两者都会引起免疫抑制和胸腺萎缩。 雌激素也有 与人类某些自身免疫性疾病明显相关 啮齿动物，而二恶英暴露已被证明会诱导某些标记物 的超免疫力。 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显着 这些药物在药理学或环境方面相似 相关剂量。 与皮质类固醇不同，单剂量 2,3,7,8- 四氯二苯并二恶英 (TCDD) 或 17β-戊酸雌二醇 (E2) 小鼠会导致萎缩，需要几天的时间才能显现出来，但是 持续数周，似乎与非胸腺干有关 细胞减少。 这两种药物都通过以下方式调节其影响： 它们的特定受体，芳烃受体 (AhR) 或雌激素 受体（ER），是参与调节的转录因子 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，而且与皮质类固醇或辐射不同，还会诱发 肝脏淋巴细胞数量增加，其中许多表达 T 细胞受体 通常在选定的小鼠品系的周围删除。 长的 一系列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，从而促进 自身免疫性疾病。 这些受体的抑制剂（部分或 完全拮抗剂）延迟或逆转正常的年龄相关胸腺萎缩？ 这些抑制剂会预防或延缓自身免疫性疾病吗？ 具体来说，将针对胸腺的作用机制进行研究。 通过确定细胞类型，这些药物诱导萎缩 在胸腺和胸腺干细胞中表达这些受体 隔间。 在确定对萎缩至关重要的时间点 诱导或恢复时，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 元素，i 被认为是近端候选的细胞类型 目标。 特定抗雌激素（如 ICI）的剂量测定 164,384）和部分 TCDD 拮抗剂（例如，α-萘黄酮）可以 将确定这些试剂防止萎缩诱导的作用。 这 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性萎缩 被确定。 这两种物质引起的肝淋巴细胞数量增加 试剂将通过使用干细胞进行表型，包括确定 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，或者它们是否是迁移者。 是否描述了抑制剂 以上，作为可以预防胸腺萎缩的剂量，可以预防 将检查这些肝脏淋巴细胞的外观。 研究将扩展至自身免疫性疾病的可能性 E2 和 TCDD 在成人自身免疫性疾病中的产生或加速 型号（SWR x NZB、SLE 型号）。 B6 x AJ 小鼠围产期暴露模型 新生儿出生 3 天后出现器官特异性自身免疫性疾病 还将检查胸腺切除术。