FETAL TROPHOBLASTS MAINTAIN MATERNAL TOLERANCE

保持遗传多样性有很强的选择压力， 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和胎儿之间的耐受性 “同种异体移植”。 由于母亲的宽容是如此重要，一些 重叠机制无疑是重要的，不仅是为了防止 启动免疫反应，而且使损伤最小化 任何可能无意中引发的反应。 马特热纳尔 接受胎儿“同种异体移植物”的发生， 免疫抑制或甚至对父系抗原的特异性耐受。 一 怀孕的女性可以拒绝来自男性伴侣的组织， 对发育中的胎儿有不良影响。 几十年的研究表明， 抗原特异性和抗原非依赖性模型的数量来解释 母体对胎儿同种异体移植物的这种组织特异性接受 免疫系统 在本提案中，我们将直接测试两个相关的， 抗原特异性机制，可能有助于组织特异性 发育中胎儿的耐受性。 这些基本框架 实验的关键在于， 母体耐受性和引起胎盘排斥将建立 这些组成部分在维持公差方面的相对重要性 本土国家。 有待检验的假设是胎儿滋养层细胞接触 与母体免疫系统通过两种机制提供保护 这与它们向母体T细胞呈递抗原的能力有关。 我们 建议在正常情况下，胎儿滋养层细胞的尾巴， 有效地激活幼稚母体T细胞。 如果母体T细胞 当滋养层细胞被激活时，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细胞死亡进行细胞扩增，或 删除。 这一假设将通过强迫转基因植物 靶MHC抗原和/或“共刺激物”分子的表达。 表达将由调节滋养层的启动子控制- 特异性激素表达。 滋养层细胞在触发 抗原依赖性T细胞死亡的途径将通过使用 该途径缺陷的突变小鼠品系（LPR和GLD）。 这些 小鼠容易患自身免疫性疾病， 受体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的 证据表明，这些机制中的任何一种在维持 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.