Influence of maternal antigens on transplant rejection

描述（申请人提供）：移植生物学家的“圣杯”是在不对受体进行广泛免疫抑制治疗的情况下实现同种异体移植的长期存活。这种移植耐受性在妊娠期间自然规律地实现。几项研究提供的证据表明，成年人对非遗传性母体抗原（NIMA）表现出一定程度的免疫耐受性。然而，这种现象背后的机制仍然是未知的。对这一问题的透彻理解可能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。我们设计了一个小鼠转基因模型来阐明后代对NIMA耐受的机制。在该模型中，NIMA是MHC I类分子Kb，并且后代表达T细胞受体转基因抗Kb。非NIMA暴露的小鼠在10天内排斥Kb+心脏移植。相比之下，Kb+心脏移植在NIMA小鼠中享有长期存活。在NIMA小鼠中未发现抗Kb T细胞的缺失和抗Kb TCR表面表达的减少，从而排除了缺失机制。与对照NE小鼠相比，来自心脏移植的NIMA小鼠的T细胞在体外暴露于Kb+刺激物，不分泌炎性细胞因子（IL-2，gIFN），但产生高水平的IL-4细胞因子。最后，在NIMA小鼠中观察到的致耐受性效应通过体内消耗CD 4+（而不是CD 8+）T细胞而消除。因此，在妊娠和/或哺乳期间暴露于NIMA Kb MHC I类的小鼠通过涉及CD 4 + T细胞的主动调节过程变得对这种同种异体抗原耐受。本提案的主要目的是阐明：1）胎儿和/或新生小鼠暴露于NIMA的机制，2）暴露于NIMA的小鼠对这些同种异体抗原耐受并接受相应心脏同种异体移植的机制。为了解决这些问题，我们计划实现以下具体目标：具体目标1。检测和确定胎儿、新生儿、断奶仔猪以及幼龄和成年后代中不同时间点存在的母体细胞的性质。具体目标2。研究NIMA小鼠的抗Kb同种异体反应。具体目标3。阐明T细胞对NIMA耐受的机制。NIMA效应的应用范围非常广泛，包括脐带血干细胞移植、尸体器官移植以及非移植领域（如自身免疫）和使用自身抗原肽的抗肿瘤疫苗接种方法的开发，这两个领域都可能受益于对NIMA耐受性基本机制的理解。

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.