Influence of maternal antigens on transplant rejection

描述(申请人提供)：移植生物学家的“圣杯”是在不对受者进行广泛的免疫抑制治疗的情况下实现同种异体移植的长期存活。这种移植耐受通常是在怀孕期间自然实现的。一些研究提供的证据表明，成年个体对非遗传母体抗原(NIMA)表现出一定程度的免疫耐受。然而，这种现象背后的机制仍不清楚。对这一问题的透彻理解可能会为设计模仿这种自然形式的移植耐受的选择性免疫疗法提供基础。我们设计了一种小鼠转基因模型，以阐明后代对NIMA耐受的机制。在这个模型中，NIMA是MHC I类分子，KB及其后代表达T细胞受体转基因抗KB。未暴露于NIMA的小鼠在10天内排斥KB+心脏移植。相比之下，Kb+心脏移植在尼玛小鼠身上可以长期存活。在NIMA小鼠中没有发现抗KB T细胞的缺失和抗KB TCR表面表达的减少，从而排除了缺失的机制。与对照NE小鼠相比，心脏移植NIMA小鼠的T细胞在体外暴露于KB+刺激物后不分泌炎性细胞因子(IL-2、g干扰素)，但产生高水平的IL-4细胞因子。最后，体内的CD4+(但不是CD8+)T细胞的耗尽消除了在NIMA小鼠身上观察到的耐受效应。因此，在怀孕和/或哺乳期间暴露于NIMA KB MHC I类的小鼠，通过涉及CD4+T细胞的主动调节过程，对这种同种异体抗原产生了耐受性。这一建议的主要目的是阐明：1)胎儿和/或新生小鼠暴露于NIMA的机制，以及2)暴露于NIMA的小鼠对这些同种异体抗原产生耐受并接受相应的心脏移植的机制。为了解决这些问题，我们计划了以下具体目标：具体目标1.检测和确定胎儿、新生儿、断奶婴儿以及幼年和成年后代在不同时间点存在的母体细胞的性质。具体目的2.研究抗KB同种异体免疫反应。具体目的3.阐明T细胞对NIMA耐受的机制。NIMA效应的应用范围很广，包括脐带血干细胞移植、身体器官移植以及自身免疫等非移植领域，以及使用自身抗原肽的抗肿瘤疫苗接种方法的开发，这两种方法都可能受益于对NIMA耐受基本机制的了解。

DESCRIPTION (provided by applicant): The "holy grail" of transplant biologists is to achieve long-term survival of an allogeneic transplant without widespread immunosuppressive treatment of the recipient. Such transplantation tolerance is regularly achieved in nature during pregnancy. Several studies have provided evidence showing that adult individuals display some degree of immune tolerance towards noninherited maternal antigens (NIMA). However, the mechanisms underlying this phenomenon are still unknown. A thorough understanding of this issue is likely to provide the basis for the design of selective immune therapies mimicking this natural form of transplantation tolerance. We have designed a mouse transgenic model to elucidate the mechanisms underlying the tolerance of offspring to NIMA. In this model the NIMA is a MHC class I molecule, Kb and the offspring express a T cell receptor transgene anti-Kb. Non-NIMA exposed mice rejected Kb+ heart transplants in 10 days. In contrast, Kb+ cardiac transplants enjoy long-term survival in NIMA mice. No deletion of anti-Kb T cells and no reduction of anti-Kb TCR surface expression was found in NIMA mice, thereby excluding a deletional mechanism. In contrast to control NE mice, T cells from heart-transplanted NIMA mice exposed in vitro to Kb+ stimulators secreted no inflammatory cytokines (IL-2, gIFN) but produced high levels of IL-4 cytokines. Finally, the tolerogenic effect observed in NIMA mice was abrogated by in vivo depletion of CD4+ (but not CD8+) T cells. Therefore, mice that have been exposed to NIMA Kb MHC class I during pregnancy and/or breast feeding have become tolerant to this alloantigen via an active regulatory process involving CD4+ T cells. The main objectives of this proposal are to elucidate: 1) the mechanisms by which the fetus and/or newborn mouse becomes exposed to NIMA and, 2) the mechanisms by which NIMA-exposed mice are rendered tolerant to these alloantigens and accept corresponding heart allotransplants. To address these questions, we plan the following specific aims: Specific aim 1. To detect and determine the nature of maternal cells present at different time points in fetuses, newborns, weanlings, as well as young and adult offspring. Specific aim 2. To investigate the anti-Kb alloresponse in NIMA mice. Specific aim 3. To elucidate the mechanisms underlying T cell tolerance to NIMA. The implications of the NIMA effect for a variety of applications are numerous, and include cord blood stem cell transplantation, cadaveric organ transplantation as well as in non-transplant fields such as autoimmunity, and development of antitumor vaccination approaches using "self antigenic peptides, both of which may benefit from an understanding of the basic mechanisms of NIMA tolerance.