Mechanisms ot Maternal Immune Tolerence

描述(申请人提供)：异基因胎儿如何避免母体 怀孕期间的免疫排斥不仅是突出的问题之一 在当代免疫学中，现在也被认为具有重大的临床意义 与疾病的相关性，如反复自然流产和 子痫前期，以及在器官移植方面的应用。虽然 人们普遍认为，母体免疫系统是知道的？那就是 胎儿和胎盘是存在的，到目前为止，研究只集中在CD8+T细胞 和B细胞，因此没有解决潜在的反应性行为 CD4+T辅助细胞，淋巴细胞亚群可能扮演最重要的角色 在任何形式的抗原特异性耐受诱导中发挥作用。在这里，我们将 直接表征母体CD4+和CD8+T细胞的反应 利用转基因小鼠获得定位表达的抗原 我们最近成功地表达了具有良好特性的模型抗原 胎盘组织中的卵清蛋白(目标1)。该系统的使用还将使 美国测试孕妇对胎儿和胎盘的耐受性是否在当地 或全身性，以及是否涉及效应器或效应器手臂的衰减 对免疫反应的影响。抗原提呈细胞(APC)的性质 怀孕的子宫是另一个几乎没有被探索的领域，尽管 这些细胞在调节耐受诱导中的中心作用。因此，我们将 描述APC的行为和抗原提呈能力 怀孕的子宫，专注于常驻树突状细胞，它们已经 在小鼠身上完全没有特征(目标2)。最后，我们描述了这一代 直接从培养的小鼠滋养层细胞转化为新的细胞系 滋养层干细胞。因为这些转化的滋养层细胞在 未怀孕的同种异体小鼠皮下注射后，它们提供了 分析滋养层细胞相对重要性的强大试剂， 子宫环境与妊娠激素状态的关系 母体容忍(目标3)。

Description (provided by applicant): How the allogeneic fetus avoids maternal immune rejection during pregnancy is not only one of the outstanding questions in contemporary immunology, but is also now recognized to have major clinical relevance towards diseases such as recurrent spontaneous abortion and preeclampsia, as well as application towards organ transplantation. Although it is generally accepted that the maternal immune system is ?aware? that the fetus and placenta exist, studies to date have only focused on CD8+ T cells and B cells, and thus have not addressed the behavior of potentially reactive CD4+ T helper cells, the lymphocyte subset likely to play the most important role in any form of antigen-specific tolerance induction. Here, we will directly characterize the responses of both maternal CD4+ and CD8+ T cells towards a placentally expressed antigen, taking advantage of transgenic mice we have recently made that express the well-characterized model antigen ovalbumin in placental tissues (Aim 1). The use of this system will also allow us to test whether maternal tolerance towards the fetus and placenta is local or systemic, and whether it involves attenuation of affector or effector arms of the immune response. The nature of antigen presenting cells (APCs) in the pregnant uterus is another area that is virtually unexplored, despite the central role of these cells in regulating tolerance induction. Thus, we will characterize the behavior and antigen-presenting capacity of APCs in the pregnant uterus, focusing on resident dendritic cells, which have been completely uncharacterized in mice (Aim 2). Lastly, we describe the generation of novel transformed murine trophoblast cell lines directly from cultured trophoblast stem cells. Since these transformed trophoblasts are rejected in non-pregnant allogeneic mice following subcutaneous injection, they provide a powerful reagent for dissecting the relative importance of trophoblasts, the uterine environment, and the hormonal state of pregnancy in establishing maternal tolerance (Aim 3).