Lentiviral expression of MHC II antigens at the maternal-fetal interface

描述（由申请人提供）：尽管胎盘哺乳动物在免疫学上是外来的，但它们不会识别和排斥它们的婴儿。显然，母亲拒绝胎儿的“失败”对生命至关重要，然而，尽管有50多年的积极研究，围绕母胎免疫耐受仍有许多谜团。在可能在建立胎儿免疫耐受中起作用的许多因素中，最可能是关键的因素之一涉及与母体免疫系统直接接触的胚外结构中主要组织相容性分子I型和II型（MHC I和II）的表达。特别是，已经注意到滋养层不表达MHC II，并且已经表明这种缺乏对母体耐受性至关重要。虽然这个理论很有趣，但它从未经过实验验证。我们建议使用一种新的方法，利用慢病毒操纵基因表达在胚胎外组织，以迫使异常表达的MHC II表面抗原在母胎界面的小鼠。通过这样做，我们将建立一个实验系统，使我们能够充分探索滋养层中缺乏MHC II是否对成功怀孕至关重要。我们预计，这些实验将最终导致理解母胎免疫耐受的重大进展。反过来，这将有助于理解和治疗免疫介导的妊娠失败。更广泛地说，对免疫耐受的更好理解也将与移植生物学和癌症免疫学相关。公共卫生相关性：母体对胎儿的免疫耐受性知之甚少。目前的提议旨在使用一种新技术来测试一种主要但未经证实的理论，即胎儿如何被母亲免疫耐受。这项工作的结果预计将对生殖免疫学以及移植和癌症生物学具有重大意义。

DESCRIPTION (provided by applicant): Despite the fact that they are immunologically foreign, placental mammals do not recognize and reject their babies. Clearly, "failure" of the mother to reject the fetus is essential to life and yet, despite more than fifty years of active research, there are still many mysteries surrounding maternal-fetal immune tolerance. Among the many factors that may play a role in establishing immune tolerance of the fetus, one of the most likely to be critical relates to the expression of the Major Histocompatibility molecules Type I and II (MHC I and II) in the extra-embryonic structures that come into direct contact with the maternal immune system. In particular, it has been noted that the trophoblast does not express MHC II, and it has been suggested that this lack is crucial to maternal tolerance. Although this theory is intriguing, it has never been experimentally tested. We propose to use a novel method that utilizes lentivirus in to manipulate gene expression in extraembryonic tissues in order to force the aberrant expression of MHC II surface antigens at the maternal-fetal interface in mice. By so doing, we will establish an experimental system that will allow us to fully explore whether the lack of MHC II in the trophoblast is critical to successful pregnancy. We anticipate that these experiments will ultimately lead to a major advance in understanding maternal-fetal immune tolerance. This, in turn, will be relevant to understanding and treating immune-mediated pregnancy failure. More broadly, an improved understanding of immune tolerance will be relevant in transplantation biology and cancer immunology as well. PUBLIC HEALTH RELEVANCE: Maternal immune tolerance of the fetus is poorly understood. The present proposal is aimed at using a novel technology in order to test a major but unproven theory of how the fetus is immunologically tolerated by the mother. The results of this work are expected to have major significance for reproductive immunology as well as for transplant and cancer biology.