Microchimerism as AlloImmunity

描述(申请人提供)：微嵌合体作为同种异体免疫的脐带血(CB)已经成为儿童和成人异基因移植的一种可接受的造血干细胞来源。除了现成可用之外，CB的优势还包括 对供受者人类白细胞抗原不匹配有更好的耐受性，降低慢性移植物抗宿主病的发病率/严重性。此外，最近有报道称，接受脐带血移植(CBT)治疗的血液系统恶性肿瘤患者的复发风险显著降低。CB是一种有潜力洞察人类母胎免疫学的资源，在CBT的背景下，提供了一个翻译洞察和受益的强大机会。脐带血来源于胎儿血液循环。然而，一些母体细胞在怀孕期间运输到胎儿，称为母体微嵌合体(MMC)。CBT后急性髓系白血病(AML)和急性淋巴细胞白血病(ALL)复发率的显著降低与CB-MMC密切相关，因为当CB母亲没有(父系遗传)的胎儿(CB)的HLA等位基因与CBT接受者分享时，特定的益处被观察到。然而，MMC没有被直接检查。在前几年，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。现在已经有大量证据表明Mc对人类健康的影响，既有害又有益，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一个新的维度，竞争的更新将集中在这一引人注目的主题上。我们的假设是，MMC至少在一定程度上是AML和CBT后复发率降低的原因。在开发了必要的技术并在微循环领域获得了广泛的专业知识后，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。第一个目标将建立关于CB中MMC的流行率、数量和表型的基本信息。第二个目标是研究急性髓细胞白血病和所有接受CBT的患者移植前和移植后外周血和骨髓中的CB MMC。结果将被评估与患者预后的相关性，特别是复发。Cb可能含有其他来源的Mc，例如来自母亲以前出生的Mc，第三个目标将测试任何替代的Cb Mc来源。第四个目标将检查AML和所有未接受移植的患者，以确定患者-母亲共有的HLA等位基因的频率；MMC也将在诊断时和首次缓解后进行检测。第五个目标将评估CB-MMC的功能和人类白细胞抗原靶标的特异性。总体而言，这些研究探讨了潜在母胎益处作为血液系统恶性肿瘤预防的新领域，并利用CBT提供的独特机会深入了解自然和医源性嵌合体。

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.