Maternal Tolerance to Fetal Alloantigens

描述(申请人提供)：这项研究的总体目标是了解怀孕期间母体对异基因胎儿的免疫耐受机制。母体免疫系统与同种异体胎儿移植之间的亲密性是一种无与伦比的生理状态，在这种情况下，胎儿表达的父系遗传的胎儿抗原在正常妊娠时总是被容忍的。这里提出的研究进一步调查了先前的观察结果，即小鼠和人类怀孕都会导致对父系遗传的胎儿同种异体抗原的高度特异性识别。对于主要的和次要的组织相容性抗原都是如此。在这项建议中，我们将使用转基因胎儿次要组织相容性抗原与母体CD4+和CD8+淋巴细胞相结合的小鼠模型来研究母体淋巴细胞的反应和对胎儿抗原耐受性的诱导。我们还研究了胎儿次要组织相容性抗原在人胎盘中的表达、时间和呈现。我们的具体目标是：1.确定小鼠妊娠期间产生的mhag特异性T细胞的表型和功能特性。2.确定孕期向T细胞展示胎儿抗原的抗原提呈细胞的表型和功能特性。3.探讨胎源性mhag在人妊娠过程中的表达及其功能意义。总而言之，这些研究将对母体淋巴细胞对胎儿抗原的反应产生重要的新见解，从而导致免疫适应和母婴和谐共存。这些知识反过来可以为妊娠失败的发病机制带来新的曙光，并为开发治疗药物奠定了基础，不仅可以共同对抗不孕症，还可以对抗癌症、自身免疫性疾病和移植排斥反应。 公共卫生相关性：许多医疗情况要么是由于对抗原的不当免疫耐受，如癌症，要么是由于对抗原的不当免疫耐受，如妊娠失败、自身免疫性疾病和移植排斥反应。怀孕代表着外来“移植物”和母体免疫系统之间共存的完美平衡，母体免疫系统已经适应了促进胎儿生长而不是排斥胎儿的生长。了解围绕这一独特生理状况发生的事件将有助于洞察如何缓解不孕不育、癌症和自身免疫性疾病。

DESCRIPTION (provided by applicant): The overall goal of this research is to understand the mechanisms of maternal immune tolerance to the allogeneic fetus in pregnancy. The intimacy between the maternal immune system and the fetal allograft is an unparalleled physiological situation in which paternally inherited fetal antigens expressed by the fetus are unfailingly tolerated in normal pregnancy. The studies proposed herein further investigate previous observations that both murine and human pregnancy results in highly specific recognition of paternally- inherited fetal alloantigens. This holds true for both major and minor histocompatibility antigens. In this proposal, we will employ a murine model of a transgenic fetal minor histocompatibility antigen in combination with maternal CD4+ and CD8+ lymphocytes that specifically react to this antigen to investigate maternal lymphocyte responses and induction of tolerance to fetal antigen. We also investigate the expression, timing and presentation of fetal minor histocompatibility antigens in the human placenta. Our Specific Aims are: 1. Determine the phenotypic and functional properties of mHAg-specific T cells generated during murine pregnancy. 2. Determine the phenotypic and functional properties of antigen presenting cells displaying fetal antigen to T cells during pregnancy. 3. Investigate the expression and functional significance of fetally-derived mHAg in human pregnancy. Collectively, these studies will yield important new insights into the responses of maternal lymphocytes to fetal antigen that lead to immunological adaptation and harmonious coexistence of mother and fetus. This knowledge could in turn, give new light into the pathogenesis of pregnancy failure, and proved a basis for the development of therapeutic agents, not only co combat infertility, but also cancer, autoimmune disease and transplant rejection. PUBLIC HEALTH RELEVANCE: Numerous medical situations arise from either inappropriate immune tolerance to antigen, such as cancer, or inappropriate immune intolerance to antigen, such as failed pregnancy, autoimmune disease, and transplantation rejection. Pregnancy represents a perfect balance of coexistence between a foreign "graft" and the maternal immune system that has adapted to promote the growth of the fetus rather than reject it. Understanding the events surrounding this unique physiological situation will yield insight on how infertility, cancer and autoimmune disease may be alleviated.