Genes that Mediate Tolerance to the Placental allograft

描述(申请人提供)：所有真兽类哺乳动物在怀孕期间都能耐受组织不相容组织的植入。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组织移植。对胎盘的选择性无能是免疫学尚未解开的中心谜团之一。由于胎盘是在具有良好适应性免疫系统的祖先物种中发育的，因此有理由认为这种生物发展了一种机制，以规避对滋养层的适应性免疫，而且，同样的核心机制在今天的后代中仍然存在。可以认为，维持耐受性需要一组离散的母体表达基因，而且影响这些基因的突变可能会破坏耐受性。为了探讨对胎盘的耐受性问题，我们在小鼠身上启动了饱和突变计划，使用筛查来检测禁止异基因(但不是同基因)怀孕的突变。在撰写本文时筛选出的3506只F1和F3小鼠中，已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，并最终通过位置克隆方法解决。鉴定出维持对同种异体胎儿移植选择性耐受所需的基因(S)将有几个重要的结果。首先，最终有可能利用哺乳动物怀孕期间使用的耐受系统来促进其他类型同种异体移植物的存活：这一结果将对移植医学产生重要影响。其次，相似或相同的分子系统在维持对自身的耐受性方面可能很重要，该系统的缺陷可能代表着某些自身免疫性疾病的原发损害。第三，对同种异体胎盘移植的耐受性失败可能是反复流产的原因，就像在人类和其他哺乳动物物种中看到的那样。第四，绕过耐受机制可能被用来防止正常妊娠，导致在胚泡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.