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）：作为同种异体脐带血（CB）作为同种异体脐带血（CB）的微chimerismism，已成为儿童和成人同种异体移植的造血干细胞的公认来源。除了现成的可用性外，CB的优势还包括 对供体 - 接收者HLA不匹配的耐受性和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）的血液系统恶性肿瘤的患者的复发风险大大降低。 CB是一种有可能洞悉人类母体免疫学的潜力，在CBT的背景下为转化洞察力和利益提供了有力的机会。 CB源自胎儿循环。然而，已知某些母体细胞在怀孕期间被称为孕产妇的微chimimerism（MMC）。在CBT强烈牵涉到CB MMC之后，急性髓样白血病（AML）和急性淋巴细胞白血病（ALL）的复发率显着降低，因为当胎儿的HLA等位基因（CB）的HLA等位基因（CB）没有（CB母亲）没有（Paternallyally anderally and Hermanally hlaperally hlapernally hla hla），这是益处（paternally hlapernally hlapernally-hersed hersed herserited）。但是，未直接检查MMC。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。结果，我们和其他人已经开始阐明源自母亲交换的微chimimerismismismismismismismismismismismismismismismismismismismismismismismismismismismismismismismis Regocial Stragialism（MC）。现在，根据许多因素，尤其是HLA等位基因的因素，有害和有益的MC对人类健康的影响，现在已经获得了大量证据。赋予反癌福利的潜力为阐明母亲交换的后果和竞争续约带来了新的方面，将重点放在这一引人注目的主题上。我们的假设是，MMC至少部分负责AML的复发率降低，而CBT之后全部降低。在开发了必要的技术并在MC中获得了基于广泛的专业知识之后，我们将独特地定位于直接解决这一新型调查视野，并直接转化对人类健康，并对接受同种异体移植的患者产生了直接影响。第一个目的将建立有关MMC在CB中的患病率，数量和表型的基本信息。第二个目标将研究AML中的CB MMC“体内”，以及所有接受CBT的患者在外周血和骨髓前和移植后。将评估结果与患者结局的相关性，尤其是复发。 CB可能可能包含其他MC的来源，例如，从母亲的先前出生中，第三个目标将测试任何其他CB MC来源。第四个目标将检查AML和所有尚未进行移植以确定患者母亲共享HLA等位基因的频率的患者； MMC在诊断和首次缓解后也将进行测定。 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特益处的新视野，因为血液学恶性肿瘤预防，并利用了独特的机会，可以洞悉CBT提供的自然和医源性嵌合体。