Microchimerism as AlloImmunity

微嵌合作为同种免疫

• 批准号: 9215692
• 负责人: Colleen Delaney
• 金额: $ 47.78万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9215692
• 关键词: Acute Lymphocytic Leukemia; Acute Myelocytic Leukemia; Acute leukemia; Address; Adult; Alleles; Antibodies; Antigens; Aspirate substance; Autoimmune Diseases; Biological; Biological Assay; Birth; Birth Order; Blood; Blood Circulation; Blood donor; Bone Marrow; Bone Marrow Transplantation; Cell Count; Cell Separation; Cells; Child; Chimerism; Diagnosis; Dimensions; Disease remission; Family; Fathers; Female; Fetus; Fluorescence-Activated Cell Sorting; Frequencies; Genetic Polymorphism; Genotype; HLA Antigens; Health; Hematologic Neoplasms; Hematopoietic stem cells; Homologous Transplantation; Human; Iatrogenesis; Immunology; Incidence; Inherited; Investigation; Magnetism; Malignant Neoplasms; Maternal-Fetal Exchange; Medical; Microchimerism; Mothers; Outcome; Patient-Focused Outcomes; Patients; Phenotype; Positioning Attribute; Pregnancy; Prevalence; Prevention; Relapse; Reporting; Resources; Severities; Siblings; Source; Specificity; Spontaneous abortion; Staining method; Stains; T-Lymphocyte; Techniques; Testing; Time; Transplant Recipients; Transplantation; Umbilical Cord Blood; Umbilical Cord Blood Transplantation; Woman; Work; Y Chromosome; abortion; adverse outcome; base; cell type; chronic graft versus host disease; fetal; healthy pregnancy; in vivo; insight; isoimmunity; novel; peripheral blood; pregnancy immunology; public health relevance; relapse risk

DESCRIPTION (provided by applicant): MICROCHIMERISM AS ALLO-IMMUNITY Umbilical cord blood (CB) has become an accepted source of hematopoietic stem cells for allogeneic transplantation in children and adults. In addition to ready availability, advantages of CB include better tolerance for donor-recipient HLA-mismatches and reduced incidence/severity of chronic graft-versus-host disease. Moreover, a significantly decreased risk of relapse in patients undergoing CB transplant (CBT) for hematologic malignancy was recently reported. CB is a resource that has the potential to generate insight into maternal-fetal immunology in humans and within the context of CBT presents a powerful opportunity for translational insight and benefit. CB derives from the fetal circulation. However, some maternal cells are known to traffic to the fetus during pregnancy, referred to as maternal microchimerism (MMc). The significantly reduced relapse rate of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) after CBT strongly implicated CB MMc because benefit was observed specifically when HLA alleles of the fetus (CB), that the CB mother did not have (paternally-inherited) were shared with the CBT recipient. MMc, however, was not examined directly. In previous years we have studied pregnancy immunology and autoimmune disease. As a result we and others have begun to elucidate biological consequences of microchimerism (Mc) originating from maternal-fetal exchange. Substantial evidence has now been garnered for Mc effects on human health, both detrimental and beneficial depending on a number of factors, especially HLA alleles. The potential to impart anti-cancer benefit brings a new dimension to elucidating consequences of maternal-fetal exchange and the competing renewal will focus on this compelling subject. Our hypothesis is that MMc is at least in part responsible for the reduced relapse rate of AML and ALL after CBT. Having developed the necessary techniques and acquired broad-based expertise in Mc we are uniquely positioned to directly address this novel investigative horizon, with direct translational applications to human health and immediate implications for patients undergoing allogeneic transplantation. The first Aim will establish essential information regarding the prevalence, quantities and phenotypes of MMc in CB. The second Aim will investigate CB MMc "in vivo" in AML and ALL patients undergoing CBT in peripheral blood and bone marrow pre and post-transplant. Results will be evaluated for correlation with patient outcome, especially relapse. CB could potentially contain other sources of Mc, for example from prior births of the mother, and the third Aim will test for any alternative CB Mc sources. The fourth Aim will examine AML and ALL patients who have not undergone transplantation to determine the frequency of patient-mother shared HLA alleles; MMc will also be assayed at diagnosis and after achieving first remission. CB MMc functionality and HLA target specificity will be evaluated in the fifth Aim. Overall these studies examine a new horizon in potential maternal-fetal benefit as hematologic malignancy prevention and exploit the unique opportunity for insight into natural and iatrogenic chimerism afforded by CBT.

描述（由申请人提供）：作为异基因免疫的微嵌合脐带血（CB）已成为儿童和成人异基因移植中公认的造血干细胞来源。除了随时可用之外，CB的优点还包括 对供体-受体HLA错配的耐受性更好，慢性移植物抗宿主病的发病率/严重程度降低。此外，最近报道了接受CB移植（CBT）治疗血液恶性肿瘤的患者复发风险显著降低。CB是一种资源，有可能产生对人类母胎免疫学的洞察力，在CBT的背景下，它为转化洞察力和益处提供了一个强大的机会。CB来源于胎儿循环。然而，已知一些母体细胞在妊娠期间运输到胎儿，称为母体微嵌合体（MMc）。CBT后急性髓性白血病（AML）和急性淋巴细胞白血病（ALL）的复发率显著降低，这与CB MMc密切相关，因为当胎儿（CB）的HLA等位基因（CB母亲没有（父系遗传））与CBT接受者共享时，特别观察到益处。然而，没有直接检查MMc。在过去的几年里，我们研究了妊娠免疫学和自身免疫性疾病。因此，我们和其他人已经开始阐明源于母胎交换的微嵌合体（MC）的生物学后果。现在已经收集了大量的证据表明Mc对人类健康的影响，这取决于许多因素，特别是HLA等位基因。赋予抗癌益处的潜力为阐明母胎交换的后果带来了新的维度，竞争性更新将集中在这一引人注目的主题上。我们的假设是，MMc至少部分负责CBT后AML和ALL复发率的降低。在开发了必要的技术并获得了Mc领域广泛的专业知识后，我们处于独特的地位，可以直接解决这一新的研究领域，直接应用于人类健康，并对接受同种异体移植的患者产生直接影响。第一个目标是建立有关CB中MMc的患病率、数量和表型的基本信息。第二个目标将研究CB MMc在AML和ALL患者中的“体内”，这些患者在移植前后的外周血和骨髓中接受CBT。将评价结果与患者结局（尤其是复发）的相关性。CB可能含有其他来源的Mc，例如来自母亲先前的分娩，第三个Aim将测试任何替代的CB Mc来源。第四个目标将检查未接受移植的AML和ALL患者，以确定患者-母亲共享HLA等位基因的频率;还将在诊断时和首次缓解后测定MMc。CB MMc功能和HLA靶点特异性将在第五个目标中进行评价。总的来说，这些研究探讨了潜在的母胎获益的新视野，如血液系统恶性肿瘤的预防，并利用独特的机会深入了解CBT提供的自然和医源性嵌合体。