Microchimerism as AlloImmunity

微嵌合作为同种免疫 脐带血（CB）已成为异基因造血干细胞的公认来源。 儿童和成人的移植。除了随时可用之外，CB的优点还包括更好地 对供受体HLA错配的耐受性和慢性移植物抗宿主的发生率/严重程度降低 疾病此外，在接受CB移植（CBT）的患者中， 最近报告了血液恶性肿瘤。CB是一种资源，有可能产生洞察力， 人类和CBT背景下的母胎免疫学为以下方面提供了强大的机会： 翻译洞察力和效益。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）。的显著 降低CBT后急性髓细胞白血病（AML）和急性淋巴细胞白血病（ALL）的复发率 强烈暗示CB MMc，因为当胎儿（CB）的HLA等位基因， CB母亲没有（父系遗传）的CBT与CBT接受者共享。然而，MMc不是 直接检查。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。作为 结果，我们和其他人已经开始阐明微嵌合体（Mc）的生物学后果， 母胎交换现在已经收集了大量证据表明Mc对人类健康的影响， 有害和有益取决于许多因素，特别是HLA等位基因。潜在的影响力 抗癌的好处带来了一个新的层面来阐明母胎交换的后果， 竞争更新将集中在这个引人注目的主题。我们的假设是MMc至少部分地 负责CBT后AML和ALL复发率的降低。开发了必要的 技术和获得广泛的专业知识，我们在MC独特的定位，直接解决这一新的 调查视野，与人类健康的直接转化应用和直接影响， 接受同种异体移植的患者。第一个目标将建立关于以下方面的基本信息： CB中MMc的患病率、数量和表型。第二个目标将研究CB MMc "体内"， 在移植前后接受外周血和骨髓CBT的AML和ALL患者。结果 将评估与患者结局的相关性，特别是复发。CB可能含有其他 Mc的来源，例如来自母亲的先前分娩，第三个Aim将测试任何替代的CB Mc 源第四个目标将检查未接受移植的AML和ALL患者， 确定患者-母亲共有HLA等位基因的频率;还将在诊断时和诊断后测定MMc 实现首次缓解。CB MMc功能和HLA靶点特异性将在第五个目标中进行评价。 总体而言，这些研究探讨了一个新的视野，在潜在的母胎受益的血液系统恶性肿瘤 预防和利用独特的机会，洞察自然和医源性嵌合体提供CBT。

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.