Microchimerism as AlloImmunity

微嵌合作为同种免疫

• 批准号: 8629071
• 负责人: Colleen Delaney
• 金额: $ 58.15万
• 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/8629071
• 关键词: Abbreviations; 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; Immunity; Immunology; Incidence; Inherited; Investigation; Magnetism; Malignant Neoplasms; Maternal-Fetal Exchange; Microchimerism; Mothers; Outcome; Patients; Phenotype; Positioning Attribute; Pregnancy; Prevalence; Prevention; Relapse; Reporting; Resources; Risk; 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; in vivo; insight; isoimmunity; novel; peripheral blood; pregnancy immunology; trafficking

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.

作为同种免疫的微嵌合现象 脐带血（CB）已成为同种异体造血干细胞的公认来源 儿童和成人移植。除了现成的可用性之外，CB 的优势还包括更好的 对供体-受体 HLA 不匹配的耐受性并降低慢性移植物抗宿主的发生率/严重程度 疾病。此外，接受CB移植（CBT）的患者复发风险显着降低 最近报道了血液系统恶性肿瘤。 CB 是一种有潜力产生洞察力的资源 人类母胎免疫学以及 CBT 的背景下为 转化洞察力和效益。 CB源自胎儿循环。然而，一些母体细胞已知 在怀孕期间贩卖给胎儿，称为母体微嵌合体（MMc）。显着地 CBT 后急性髓系白血病 (AML) 和急性淋巴细胞白血病 (ALL) 的复发率降低 强烈涉及 CB MMc，因为在胎儿 (CB) 的 HLA 等位基因时特别观察到益处，即 CB 母亲没有（父系遗传）与 CBT 接受者共享。然而MMc并没有 直接检查。前几年我们研究了妊娠免疫学和自身免疫性疾病。作为一个 结果我们和其他人已经开始阐明源自微嵌合体（Mc）的生物学后果 母胎交换。现已收集到大量证据证明 Mc 对人类健康的影响， 有害和有益取决于多种因素，尤其是 HLA 等位基因。传授的潜力 抗癌益处为阐明母胎交换的后果和 竞争性的更新将集中在这个引人注目的主题上。我们的假设是 MMc 至少部分是 导致 CBT 后 AML 和 ALL 复发率降低。开发了必要的 技术并获得了广泛的 Mc 专业知识，我们拥有独特的优势来直接解决这一新颖问题 研究视野，对人类健康有直接的转化应用和直接影响 接受同种异体移植的患者。第一个目标将建立有关 CB 中 MMc 的患病率、数量和表型。第二个目标将在“体内”研究 CB MMc 接受移植前和移植后外周血和骨髓 CBT 的 AML 和 ALL 患者。结果 将评估与患者结果（尤其是复发）的相关性。 CB 可能含有其他 Mc 的来源，例如来自母亲之前的出生，第三个目标将测试任何替代 CB Mc 来源。第四个目标将检查未接受移植的 AML 和 ALL 患者 确定患者与母亲共享 HLA 等位基因的频率； MMc 也将在诊断时和之后进行检测 实现首次缓解。 CB MMc 功能和 HLA 目标特异性将在第五个目标中进行评估。 总体而言，这些研究探讨了血液恶性肿瘤潜在母婴利益的新视野 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现象。