FETAL TROPHOBLASTS MAINTAIN MATERNAL TOLERANCE

有很大的选择压力来保持遗传多样性 脊椎动物种群。这一过程的核心是保持一种 成熟的母体免疫系统与胎儿之间的耐受性 “异体移植”。由于母性容忍是如此关键，许多人 重叠机制无疑是重要的，不仅是为了防止 启动免疫反应，但也将损害降至最低 任何可能不经意间发起的响应。马杰纳尔 接受胎儿“同种异体移植”时，没有发生任何一般情况。 免疫抑制，甚至对父系抗原的特异性耐受。一个 怀孕的女性可以拒绝来自男性伴侣的组织，而不是 对发育中的胎儿有不良影响。几十年的工作表明， 要解释的抗原特异性和抗原非依赖性模型的数量 母体对同种异体胎儿移植的这种组织特异性接受 免疫系统。在这个提案中，我们将直接测试两个相关的， 可能有助于组织特异性的抗原特异性机制 对发育中胎儿的耐受性。这些项目的基本框架 实验就是，了解必要的成分才能打破 母体耐受性和引起胎盘排斥将建立 这些组件在维持公差方面的相对重要性 原生状态。 需要检验的假设是胎儿滋养层细胞接触 母体免疫系统通过两种机制提供保护 与它们向母体T细胞呈递抗原的能力有关。我们 建议在正常情况下胎儿滋养层细胞尾部 有效激活幼稚母体T细胞。如果母体T细胞这样做 被激活，我们认为滋养层细胞限制了T细胞的能力 通过触发抗原依赖性T细胞死亡或 删除。这一假设将通过强制转基因来检验 靶MHC抗原和或“共刺激分子”的表达。 表达将由调节滋养层细胞的启动子控制- 特定的激素表达。滋养层细胞在触发中的作用 抗原依赖性T细胞死亡的途径将通过使用 缺乏该途径的突变小鼠品系(LPR和GLD)。这些 小鼠容易患自身免疫性疾病，并有肿瘤坏死因子的突变。 受体相关蛋白和肿瘤坏死因子相关蛋白，Fas和Fas配体。 这些实验的成功完成将提供第一个直接 证据表明，这两种机制中的任何一种都对维持 母体对胎儿的耐受性。

There is a strong selective pressure to maintain genetic diversity in vertebrate populations. Central to this process is maintaining a state of tolerance between the mature, maternal immune system and the fetal "allograft". Because maternal tolerance is so critical, a number of overlapping mechanisms are undoubtedly important not only to prevent the initiation of an immunological response, but also to minimize th damage from any response that might inadvertently be initiated. Matgernal acceptance of the fetal "allograft" occurs without either general immunosuppression or even specific tolerance to paternal antigens. A pregnant female can reject tissue derived from the male partner without adverse effect on the developing fetus. Decades of work have suggested a number of both antigen-specific and antigen-independent models to explain this tissue-specific acceptance of the fetal allograft by the maternal immune system. In this proposal we will directly test two related, antigen-specific mechanisms that may contribute to tissue-specific tolerance of the developing fetus. The underlying framework of these experiments is that an understanding of the components necessary to break maternal tolerance and cause placental rejection will establish the relative importance of those components in maintaining tolerance in the native state. The hypothesis to be tested is that fetal trophoblast cells in contact with the maternal immune system provide protection by two mechanisms related to their capacity to present antigens to maternal T cells. We propose that under normal conditions fetal trophoblasts tail to effectively activate naive maternal T cells. If maternal T cells do become activated, we propose that the trophoblasts limit capacity for T cell expansion by triggering an antigen-dependent T cell death or deletion. The hypothesis will be tested by forcing the transgenic expression of target MHC antigens and or "co-stimulator" molecules. Expression will be controlled by promoters that regulate trophoblast- specific hormone expression. The role of the trophoblasts in triggering a pathway of antigen-dependent T cell death will be determined by using mutant strains of mice (lpr and gld) deficient in this pathway. These mice are prone to autoimmune disease and have mutations in the TNF receptor- and TNF-related proteins, fas and fas ligand, respectively. Successful completion of these experiments would provide the first direct evidence that either of these mechanisms is important in maintaining maternal tolerance to the fetus.