Maternal Microchimerism and Neonatal Tolerance

母体微嵌合和新生儿耐受性

• 批准号: 8241412
• 负责人: William J Burlingham
• 金额: $ 39.18万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-15 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8241412
• 关键词: Abbreviations; Adult; Adverse effects; African American; Alloantigen; Allograft Tolerance; Allografting; Animal Model; Antigen-Presenting Cells; Antigens; Area; Autoimmune Process; Autoimmunity; Backcrossings; Birth; Breeding; CD8B1 gene; Caucasians; Caucasoid Race; Cell Lineage; Cells; Child; Chimerism; Clinical; Data; Daughter; Donor person; Educational process of instructing; Effector Cell; Equilibrium; Eragrostis; Ethnic Origin; Excision; Exposure to; Family; Family member; Fetus; Fracture; Funding; Goals; Graft Survival; Haplotypes; Health; Heart Transplantation; Histocompatibility Antigens Class II; Human; Immune; Immune Tolerance; Immune response; Immune system; Immunosuppressive Agents; Inbred Strains Mice; Individual; Inherited; Kidney Failure; Kidney Transplantation; Laboratories; Life; Link; Mammals; Measures; Microchimerism; Minor; Mothers; Mus; NIMA; Neonatal; Not Hispanic or Latino; Organ; Organ Transplantation; Outcome; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Pregnancy; Probability; Regulation; Regulatory T-Lymphocyte; Reliance; Reproductive Immunology; Research; Resistance; Resistance to infection; Role; Safety; Solid; Son; T cell regulation; T memory cell; T-Lymphocyte; Testing; Tetanus Toxoid; Tissues; Transgenic Mice; Transplant Recipients; Transplant Surgeon; Transplantation; Transplantation Tolerance; Work; bacterial H antigen; base; cancer risk; drug withdrawal; end-stage organ failure; fascinate; fetal; fetus cell; human subject; immunogenic; kidney allograft; mouse model; offspring; pathogen; response

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.

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，但母体/胎儿微嵌合体（来自母亲的罕见细胞在儿童中或母亲中的长期存活）在生殖免疫学、自身免疫发病机制和移植耐受性中的作用仍然是一个未探索的领域。然而，一幅图景已经开始浮现母体微嵌合体以某种方式教会发育中的适应性免疫系统如何平衡抵抗病原体的需要和保护敏感组织免受自身免疫破坏的需要。在上一个资助期间的一个关键发现是在小鼠模型中发现了母体微嵌合体水平与成年小鼠中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。这一发现被健康成年人的类似发现所证实，表明哺乳动物的一般原则，而不仅仅是“小鼠现象”。因此，我们提出了这样的假设，即母体/胎儿细胞交换导致终身微嵌合体，这可能引起耐受或致敏，这取决于嵌合体成功渗透专业抗原呈递细胞[APC]谱系的能力，从而使平衡偏向T调节细胞与T效应细胞诱导。该假设将通过3个特定目的进行检验：1）[人]，以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，该状态如何与母体微嵌合体相关，以及哪些同种抗原特异性T细胞有助于NIMA耐受[T调节细胞]或致敏[T效应细胞]; 2）[小鼠]确定特定Mc+谱系在NIMA特异性耐受性或致敏中的作用，以及是否仅受体，或受体和供体两者（乘客）CD 4和CD 8 T细胞影响NIMA对器官移植结局的影响（相互调节假说）;和3）[人]以确定受体和/或供体的移植前胎儿/母体免疫状态是否预测HLA-单倍型相同的活体相关供体肾移植中的肾同种异体移植物结果。自从首次提交该竞争性更新申请以来，我们已经发现，通过简单地测量间接途径抗NIMA Treg活性的水平，可以在移植前准确地预测小鼠心脏移植对表达“NIMA”的供体的耐受性[Dutta et al.，AJT 2011，in press].这项研究的意义在于，如果成功，它不仅可以识别小鼠和人类天然同种异体耐受的关键细胞成分，而且还可以使移植外科医生选择具有高成功率的活体相关患者-供体组合，同时避免在临床耐受性试验中致敏。 公共卫生相关性：成功的怀孕取决于免疫耐受的自然机制，以确保胎儿和母亲的健康，直到分娩。然而，即使在分离后，母亲和婴儿仍然在体内保留少量的胎儿或母体细胞，显然无视宿主免疫系统的监视。这项研究旨在确定胎儿-母体细胞接受的机制，以及是否可以利用对这种自然“移植”的获得性耐受来为器官移植受体造福。我们还将研究种族在对母体细胞反应中的作用，以及这是否有助于解释在非裔美国人和西班牙裔非高加索受试者中观察到的肾移植存活率较低的原因。