Maternal Tolerance to Fetal Alloantigens

描述（由申请人提供）：本研究的总体目标是了解孕妇对异体胎儿的免疫耐受机制。母体免疫系统和胎儿同种异体移植物之间的亲密关系是一种无与伦比的生理状况，在正常妊娠中，胎儿表达的父亲遗传的胎儿抗原始终是耐受的。本文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异体抗原的高度特异性识别。这对主要和次要组织相容性抗原都成立。在这项提议中，我们将采用转基因胎儿小组织相容性抗原与母体CD4+和CD8+淋巴细胞结合的小鼠模型，研究母体淋巴细胞对该抗原的反应和对胎儿抗原的耐受诱导。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. 确定抗原提呈细胞在妊娠期间向T细胞展示胎儿抗原的表型和功能特性。3. 探讨胎源性mHAg在人妊娠中的表达及其功能意义。总之，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，从而导致母亲和胎儿的免疫适应和和谐共存。反过来，这一知识可以为了解妊娠失败的发病机制提供新的线索，并为开发治疗药物奠定基础，不仅可以治疗不孕症，还可以治疗癌症、自身免疫性疾病和移植排斥反应。

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.