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.

微chimerism是同质子免疫 脐带血（CB）已成为同种异体造血干细胞的公认来源 儿童和成人的移植。除了现成的可用性外，CB的优势还包括更好 对供体供应HLA不匹配的耐受性和慢性移植物宿主的发病率/严重程度降低 疾病。此外，接受CB移植（CBT）的患者的复发风险大大降低了 最近报道了血液学恶性肿瘤。 CB是一种有可能洞悉的资源 在人类和CBT的背景下，母亲及其免疫学为 翻译洞察力和利益。 CB源自胎儿循环。但是，某些母体细胞是已知的 在怀孕期间访问胎儿，称为母体微chimerism（MMC）。显着 CBT后，急性髓样白血病（AML）和急性淋巴细胞白血病（ALL）的复发率降低 强烈暗示CB MMC，因为当胎儿的HLA等位基因（CB）（CB）时，会特别观察到益处 CB母亲没有与CBT接收者共享（父亲息）。但是，MMC不是 直接检查。在过去的几年中，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源自微思维（MC）的生物学后果 母亲交换。现在，已经获得了大量证据来获得MC对人类健康的影响 有害和有益的，具体取决于许多因素，尤其是HLA等位基因。传授的潜力 反癌利益为阐明母亲交换的后果和 竞争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 负责CBT后AML的复发率降低。开发了必要的 技术并获得了MC的广泛专业知识，我们在直接解决这部小说方面是独特的。 调查视野，直接转化为人类健康，直接对 接受同种异体移植的患者。第一个目标将建立有关 MMC在CB中的患病率，数量和表型。第二个目标将调查CB MMC“体内” AML以及所有接受CBT的患者在外周血和骨髓前和移植后。结果 将评估与患者结局的相关性，尤其是复发。 CB可能包含其他 MC的来源，例如母亲的先前出生，第三个目标将测试任何替代CB MC 来源。第四目标将检查AML和所有未接受移植到的患者 确定患者母亲共享HLA等位基因的频率； MMC也将在诊断和之后进行测定 实现第一缓解。 CB MMC功能和HLA目标特异性将在第五目标中进行评估。 总体而言，这些研究研究了潜在的母亲福利益处的新视野作为血液系统恶性肿瘤 预防并利用CBT提供的自然和医源性嵌合体的独特机会。