Genes that Mediate Tolerance to the Placental allograft

描述（由申请人提供）：所有真足哺乳动物在怀孕期间耐受组织不相容组织的移植。然而，母体免疫系统仍然有能力抵抗感染或排斥其他形式的同种异体组织移植。对胎盘的选择性能量是免疫学的核心未解之谜之一。由于胎盘是在一个具有适应性免疫系统的祖先物种中发育的，因此我们有理由认为这种生物发展了一种机制来规避对滋养细胞的适应性免疫，而且，同样的核心机制在今天的后代中仍然存在。这可能被认为是不言自明的，一组离散的母系表达基因是维持耐受性所必需的，而且，影响这些基因的突变可能会破坏耐受性。为了解决胎盘耐受问题，我们在小鼠中启动了饱和诱变程序，使用筛选来检测禁止同种异体（但不是同基因）妊娠的突变。截至撰写本文时，已在3506只F1和F3小鼠中鉴定出三个显性突变。这些突变和其他出现的突变将被绘制出来，并最终通过定位克隆方法得到解决。鉴定维持对胎儿同种异体移植物选择性耐受所需的基因将产生几个重要的后果。首先，最终有可能利用哺乳动物妊娠期间利用的耐受性系统来促进其他类型同种异体移植物的存活：这一结果将在移植医学中产生重要影响。其次，相似或相同的分子系统可能对维持对自身的耐受性很重要，并且该系统的缺陷可能代表某些自身免疫性疾病的原发性病变。第三，在人类和其他哺乳动物中，对同种异体胎盘的耐受失败可能是导致反复流产的原因。第四，可以通过规避耐受性机制来阻止正常妊娠，导致囊胚植入后几天内终止妊娠。

DESCRIPTION (provided by applicant): All eutherian mammals tolerate the engraftment of histoincompatible tissue during pregnancy. Yet, the maternal immune system remains competent to repel infection or to reject other forms of tissue allograft. Selective anergy to the placenta is one of the central unsolved mysteries of immunology. Since the placenta developed in an ancestral species that was endowed with a competent adaptive immune system, it is reasonable to suppose that this organism developed a mechanism for the circumvention of adaptive immunity to the trophoblast, and further, that the same core mechanism persists in its descendants today. It may be taken as axiomatic that a discrete set of maternally expressed genes is required for the maintenance of tolerance, and further, that mutations affecting these genes could disrupt tolerance. To approach the question of tolerance to the placenta, we have initiated a program of saturation mutagenesis in mice, employing a screen to detect mutations that forbid allogeneic (but not syngeneic) pregnancy. Three dominant mutations have been identified among 3506 F1 and F3 mice screened as of this writing. These mutations, and others that emerge, will be mapped and ultimately resolved through positional cloning methods. The identification of the gene(s) required for maintenance of selective tolerance to the fetal allograft will have several important consequences. First, it might ultimately be possible to take advantage of the toleragenic system utilized during mammalian gestation to promote the survival of other types of allograft: an outcome that would have important ramifications in transplantation medicine. Second, a similar or identical molecular system might be important in the maintenance of tolerance to self, and defects of the system might represent primary lesions in certain autoimmune diseases. Third, failure of tolerance to the placental allograft might be responsible for recurrent abortion as witnessed in humans and other mammalian species. Fourth, circumvention of the toleragenic mechanism might be used to prevent normal gestation, leading to termination of pregnancy within a few days following implantation of the blastocyst.