CONSEQUENCES OF THYMIC ATROPHY INDUCED BY TCDD AND E2

雌激素和二恶英会导致免疫抑制和胸腺萎缩。 雌激素也与自身免疫性疾病有关，而二恶英 已被证明与高免疫性标志物的诱导有关。 这个应用程序的首要目标是识别准确的 与胸腺相关的胸腺内发育的改变(S) 由上述药物和相关化合物引起的萎缩，以及通过使用 含有适当报告结构的转基因小鼠，以识别 胸腺内特定的造血细胞或基质细胞，其中 二恶英受体(AhR)或雌激素受体(ER)被激活以 影响T细胞发育。具体的细胞靶点将得到确认 通过使用缺乏AhR或其中之一或两者的转基因小鼠 定义的急诊室。小鼠T细胞受阻后辐射诱导的造血嵌合体 细胞发育，缺乏受体，含有受体报告 构建，将被用来精确定义萎缩的细胞靶点。 一旦定义了这些目标单元格，并且更改( 增殖/分化停滞或凋亡)确认， 这些细胞通过AhR或ER激活产生特定的基因产物 将会被澄清。第二个目标是确定是否存在 TCDD、E_2或DES致胸腺过早萎缩之间的直接联系 以及自身免疫的发展，如果是这样，其机制是什么 这两个过程之间的关系。这样的研究将提供洞察力 雌激素如何促进自身免疫，以及可能存在的风险 长期服用雌激素化合物和“环境” 雌激素。具体地说，这项提案旨在确定是什么改变了T- 外周和胸腺中的细胞群与狼疮样病变有关 NZB×SWR中E2、DES和TCDD促进的自身免疫性肾炎 (SNF/1)小鼠模型。胸腺萎缩是否与疾病有关 诱导，也将通过暴露前和暴露后的胸腺切除术来探索 通过确定诱导病理所需的最小剂量 关联的标记。

Estrogens and dioxins induce immunosuppression and thymic atrophy. Estrogens also are associated with autoimmune disease, while dioxin has been shown to be associated with induction of markers of hyper-immunity. The first aims of this application is identification of the precise alteration(s) in intrathymic development that are associated with thymic atrophy induced by the above agents and related compounds, and, by using transgenic mice containing appropriate reporter constructs, to identify the particular intra-thymic hemopoietic or stromal cells in which either the dioxin receptor (AhR) or the estrogen receptors (ER) are activated to affect T-cell development. The specific cellular targets will be confirmed by use of transgenic mice lacking either the AhR or one or both of the defined ERs. Radiation induced hemopoietic chimeras of mice arrested in T- cell development, lacking receptor, and containing receptor reporter constructs, will be used to precisely define the cell target for atrophy. Once these target cells are defined, and the alteration (either proliferation/differentiation arrest or apoptosis) confirmed, the particular gene products produced in these cells by AhR or ER activation will be elucidated. The second aim is to determine whether there is a direct link between premature thymic atrophy induced by TCDD or E2 or DES and the development of autoimmunity, and if so, what is the mechanistic relation between the two processes. Such studies would provide insight into how estrogens contribute to autoimmunity, and what the risk might be of chronic administration of estrogenic compounds and 'environmental' estrogens. Specifically, this proposal seeks to determine what altered T- cell populations in the periphery and thymus contribute to the lupus-like autoimmune nephritis facilitated by E2, DES, and TCDD in the NZB x SWR (SNF/1) murine model. Whether thymic atrophy is essential to disease induction, will be explored by pre and post-exposure thymectomy, as well as by determining the minimal doses needed to induce the pathology associated markers.