Maternal Microchimerism and Neonatal Tolerance

描述（由申请人提供）：尽管在人类和动物模型中进行了数十年的研究，母体/胎儿微嵌合（来自母亲的稀有细胞在儿童体内或儿童在母亲体内的长期存活）在生殖免疫学、自身免疫的发病机制和移植耐受中的作用仍然是一个很大程度上未被探索的领域。然而，一幅图景已经开始浮现——母体微嵌合在某种程度上教会了发育中的适应性免疫系统如何在抵抗病原体的需要与保护敏感组织免受自身免疫破坏的需要之间取得平衡。在之前的资助过程中，一个重要的发现是在小鼠模型中发现了母体微嵌合水平与成年小鼠非遗传性母体抗原或NIMA特异性T调节细胞水平之间的联系。这一发现与健康成年人的类似发现相一致，表明哺乳动物的普遍规律，而不仅仅是“老鼠现象”。因此，我们提出假设，母体/胎儿细胞交换导致终身微嵌合，可能引起耐受性或致敏性，这取决于嵌合能否成功渗透专业抗原呈递细胞（APC）谱系，从而使T调节细胞和T效应细胞诱导的平衡发生变化。这一假设将通过3个特定目的进行检验：1)[人类]确定不同种族背景的健康家庭中个体家庭成员的NIMA特异性免疫状态，这种状态与母体微嵌合的关系，以及哪些同种异体抗原特异性T细胞有助于NIMA耐受性[T调节细胞]或致敏性[T效应细胞]；2)[小鼠]确定特定Mc+谱系在NIMA特异性耐受或致敏中的作用，以及受体单独或受体和供体（乘客）CD4和CD8 T细胞是否影响NIMA对同种异体器官移植结果的影响（相互调节假说）；3)[人类]确定移植前受体和/或供体的胎儿/母体免疫状态是否能预测hla -单倍相同活体供体肾移植的移植结果。自首次提交这一竞争性更新申请以来，我们已经发现，通过简单测量间接途径抗NIMA Treg活性的水平，可以在移植前准确预测小鼠心脏移植对表达“NIMA”供体的耐受性[Dutta等人，AJT 2011, in press]。这项研究的意义在于，如果成功，它不仅将确定小鼠和人类天然同种异体耐受性的关键细胞成分，而且还将使移植外科医生能够在临床耐受性试验中选择高概率成功的活体相关患者-供体组合，同时避免致敏。

DESCRIPTION (provided by applicant): Despite decades of work in humans and animal models, the role of maternal/fetal microchimerism (the long term survival of rare cells from mothers in children or children in mothers) in reproductive immunology, pathogenesis of autoimmunity, and transplantation tolerance remains a largely unexplored area. A picture has begun to emerge, however-that maternal microchimerism somehow teaches the developing adaptive immune system how to balance the need for pathogen resistance against the requirement to protect sensitive tissues from autoimmune destruction. A key discovery in the course of the previous funding period was the finding in a mouse model of a link between the level of maternal microchimerism and the level of T regulatory cells specific for non-inherited maternal antigens or NIMA in adult mice. This discovery was paralleled by similar findings in healthy adult humans, suggesting general principles in mammals and not simply a 'mouse phenomenon'. Therefore we propose the hypothesis that maternal/fetal cell exchanges result in lifelong microchimerism that may evoke either tolerance or sensitization, depending on the ability of the chimerism to successfully infiltrate professional antigen-presenting cell [APC] lineages and thereby tip the balance in favor of T regulator vs. T effector cell induction. This hypothesis will be tested by means of 3 Specific Aims: 1)[Human] to determine in healthy families of different ethnic backgrounds the NIMA-specific immune status of individual family members, how this status is related to maternal microchimerism, and which alloantigen- specific T cells contribute to NIMA tolerance [T regulatory cell] or sensitization [T effector cell]; 2) [Mouse] to determine the role of particular Mc+ lineages in NIMA-specific tolerance or sensitization, and whether recipient only, or both recipient and donor (passenger) CD4 and CD8 T cells influence the NIMA effect on organ allograft outcome (the mutual regulation hypothesis); and 3) [Human] to determine if pre-transplant fetal/maternal immune status of recipient and/or donor predicts renal allograft outcome in HLA-haplo-identical living-related donor renal transplantation. Since the first submission of this competitive renewal application, we have discovered that mouse heart transplant tolerance to a "NIMA"-expressing donor can be accurately predicted prior to transplantation by simply measuring the level of indirect pathway anti- NIMA Treg activity [Dutta et al., AJT 2011, in press]. The significance of the research is that if successful, it will not only identify the key cellular components of natural allotolerance in mice and humans, but it will also enable transplant surgeons to select live-related patient-donor combinations with a high probability of successful outcome while avoiding sensitization in clinical tolerance trials. PUBLIC HEALTH RELEVANCE: Successful pregnancy depends on natural mechanisms of immunologic tolerance that insure the health of the fetus and mother until delivery. However, even after separation, mother and baby continue to harbor small numbers of fetal or maternal cells in their body, in apparent defiance of surveillance by the host immune system. This study seeks to determine the mechanisms of fetal-maternal cell acceptance, and whether acquired tolerance to this natural "transplant" can be exploited for the benefit of the organ transplant recipient. We will also investigate the role of ethnicity in the response to maternal cells and whether this can help explain the lower rates of kidney graft survival observed in African-American and Hispanic non- Caucasian subjects.