Genes that Mediate Tolerance to the Placental allograft

介导同种异体胎盘移植物耐受的基因

• 批准号: 6892326
• 负责人: BRUCE A BEUTLER
• 金额: $ 57.34万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6892326
• 关键词: gene mutation; genetic mapping; genetic regulation; immune tolerance /unresponsiveness; immunogenetics; laboratory mouse; molecular cloning; nucleic acid sequence; placenta; pregnancy immunology

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.

描述（由申请方提供）：所有真兽目哺乳动物在妊娠期间均耐受组织不相容性组织的植入。然而，母体免疫系统仍然有能力排斥感染或排斥其他形式的组织同种异体移植物。胎盘的选择性无反应性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展起来的，因此可以合理地假设这种生物体发展了一种机制来规避对滋养层的适应性免疫，并且进一步地，相同的核心机制仍然存在于今天的后代中。这可能被认为是不言自明的，一组离散的母源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破坏耐受性。为了探讨胎盘耐受性的问题，我们在小鼠中启动了一项饱和诱变程序，采用筛选来检测禁止异基因（但不是同基因）妊娠的突变。截至本文撰写时，已在筛选的3506只F1和F3小鼠中鉴定出三种显性突变。这些突变和其他出现的突变将被定位并最终通过定位克隆方法解决。对维持对胎儿同种异体移植物的选择性耐受性所需的基因的鉴定将有几个重要的结果。首先，它最终可能利用哺乳动物妊娠期间使用的耐受系统，以促进其他类型的同种异体移植物的存活：一个结果，将有重要的影响移植医学。第二，相似或相同的分子系统在维持自身免疫耐受性中可能是重要的，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，对胎盘移植物的耐受性失败可能是人类和其他哺乳动物反复流产的原因。第四，规避耐受机制可能被用来阻止正常妊娠，导致在胚泡植入后几天内终止妊娠。