Mechanisms ot Maternal Immune Tolerence

描述（申请人提供）：同种异体胎儿如何避免母体 怀孕期间的免疫排斥不仅是一个悬而未决的问题， 在当代免疫学中，但现在也被认为具有重大的临床意义， 与复发性自然流产等疾病的相关性， 先兆子痫，以及在器官移植方面的应用。虽然 一般认为母体免疫系统是？知道吗的 胎儿和胎盘存在，迄今为止的研究只集中在CD8+ T细胞 和B细胞，因此还没有解决潜在的反应性的行为， CD4+ T辅助细胞，淋巴细胞亚群可能发挥最重要的作用 在任何形式的抗原特异性耐受诱导中的作用。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， 我们最近制造了一种表达典型抗原的 胎盘组织中的卵清蛋白（Aim 1）。该系统的使用还将允许 我们测试母体对胎儿和胎盘的耐受性是否是局部的 或全身性，以及是否涉及效应器或效应器臂的衰减 免疫系统的反应。免疫球蛋白中抗原呈递细胞（APC）的性质 妊娠子宫是另一个几乎未被探索的领域，尽管 这些细胞在调节耐受诱导中的核心作用。因此，我们将 表征APC的行为和抗原呈递能力， 怀孕的子宫，重点是居民树突细胞，这已经被 在小鼠中完全未表征（目的2）。最后，我们描述了一代 新的转化鼠滋养层细胞系直接从培养的 滋养层干细胞由于这些转化的滋养层细胞被排斥， 非妊娠同种异体小鼠皮下注射后，它们提供了 作为剖析滋养层相对重要性的有力试剂， 子宫环境和怀孕的激素状态， 母体耐受性（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).