Perinatal immune development and risk of childhood acute lymphoblastic leukemia

围产期免疫发育和儿童急性淋巴细胞白血病的风险

• 批准号: 8761783
• 负责人: Xiaomei Ma
• 金额: $ 67.07万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8761783
• 关键词: 14 year old; Abbreviations; Acute Lymphocytic Leukemia; Affect; Age; Archives; B-Cell Acute Lymphoblastic Leukemia; B-Lymphocytes; Birth; Blood; Blood specimen; CD4 Positive T Lymphocytes; California; Cancer Etiology; Caring; Cell surface; Characteristics; Child; Childhood; Childhood Acute Lymphocytic Leukemia; Childhood Leukemia; Contracts; Development; Diagnosis; Disease; Environment; Environmental Risk Factor; Epidemiology; Equilibrium; Etiology; Exposure to; Fetal Tissues; Fetus; Genetic; Genotype; HLA Antigens; Habitual Abortion; Helper-Inducer T-Lymphocyte; IgE; Immune; Immune response; Immune system; Immunophenotyping; Immunosuppression; Immunosuppressive Agents; Individual; Infection; Infection Control; Influentials; Interferons; Interleukin-10; Interleukin-12; Life; Link; Literature; Malignant Childhood Neoplasm; Malignant Neoplasms; Measures; Medical; Methylation; Modality; Modeling; Mothers; Natural Killer Cells; Neonatal; Newborn Infant; Outcome; Pathway interactions; Pattern; Perinatal; Phenotype; Physicians; Placenta; Play; Pregnancy; Public Health; Regulatory T-Lymphocyte; Research; Research Project Grants; Risk; Risk Factors; Series; Serological; Siblings; Specimen; Spottings; Staging; Testing; Visit; base; cancer type; case control; cytokine; developmental genetics; epidemiology study; fetal; follow-up; immune function; killer immunoglobulin-like receptor; leukemia; maternal serum; neonate; postnatal; public health relevance; receptor; response; sample collection; transcription factor; trophoblast

DESCRIPTION (provided by applicant): Childhood leukemia is the most common childhood cancer but the causes of the disease are uncertain in the vast majority of cases. Epidemiology studies have pointed to patterns of infection being influential risk factors for leukemia - with exposure to a wide variety and number of childhood contacts (e.g., daycare and older siblings) being protective for leukemia. These associations are strongest for the pre-B cell immunophenotype of leukemia, which we will study here. New epidemiologic evidence suggests that vigorous response to infections, meaning infections that require care from medical professionals, is a risk factor for leukemia. Additionally, children who contract leukemia have a deficit of the immunosuppressive cytokine IL10 at birth when compared to control children who did not get leukemia, meaning that they enter the world with a congenital immune aberration. We hypothesize, based on these observations, that features of neonatal immune function, namely a lack of immunosuppression, are important in risk of pre-B cell acute lymphoblastic leukemia (pre-B ALL). In the current study we will further define this immunosuppressive phenotype in more detail and examine the developmental fetal genetic interaction and maternal environmental factors that influence this fetal phenotype. We will assemble a series of 500 ALL case children and their mothers, and 500 controls with their mothers to assess whether two genetic factors (HLA-C and KIR) critical in developing a supportive immune environment for a fetus within its mother can influence fetal immune status and leukemia case/control status. We will additionally assess, with 200 case mothers and 500 control mothers, whether neonatal immune function phenotype is influenced by maternal immune status during pregnancy. We will define fetal immune phenotype by additional markers besides only IL10 levels, including TGF-¿, IFN-¿, and T- regulatory cell marker - a differentially-methylated region of the critical transcription factor FOXP3. The impact of maternal cytokines and IGE levels, and KIR genotypes (along with HLA-C genotypes in the neonate) will first be assessed on neonatal immune function among controls. Both maternal and fetal immune phenotypes will then be assessed for their impact in prediction of case status. The results of this study will further defie critical characteristics in immune development that influence a cancer of the immune system. These results will benefit efforts to understand the etiology of leukemia as well aid predictive and preventative modalities for childhood leukemia, and set the stage for follow-up studies that examine postnatal factors that combine together with congenital immune immunosuppression to produce leukemia.

描述（由适用提供）：儿童白血病是最常见的儿童癌症，但在绝大多数病例中，疾病的原因是不确定的。流行病学研究表明，感染的模式受到了白血病的危险因素 - 暴露于各种各样的儿童接触（例如，日托和年龄较大的兄弟姐妹）受到白血病的保护。这些关联对于白血病的前B细胞免疫表型很强，我们将在此处研究。新的流行病学证据表明，对感染的有力反应，这意味着需要医疗专业人员护理的感染是白血病的危险因素。此外，与未患白血病的对照儿童相比，患有白血病的儿童在出生时还具有免疫抑制性的细胞因子IL10，这意味着他们以先天性的免疫结构进入了世界。根据这些观察，我们假设新生儿免疫抑制的特征，即缺乏免疫抑制，对于前B细胞急性淋巴细胞性白血病的风险至关重要。在当前的研究中，我们将更详细地定义这种免疫抑制表型，并检查影响这种胎儿表型的发育胎儿遗传相互作用和母体环境因素。我们将组装一系列的500例儿童及其母亲，并与母亲一起进行500个对照，以评估两个遗传因素（HLA-C和KIR）对于在其母亲中为胎儿提供支持的免疫环境至关重要是否可以影响胎儿免疫状态和白血病病例/控制状态。我们还将评估200例母亲和500名对照母亲，新生儿免疫功能表型是否受到怀孕期间母体免疫状态的影响。我们将通过仅IL10水平（包括TGF-€，IFN-€和T调节性细胞标记）（包括关键转录因子Foxp3的差异甲基化区域）来定义胎儿免疫表型。母体细胞因子和IgE水平以及KIR基因型（以及Neonate中的HLA-C基因型）的影响将首先在对照组之间进行新生儿免疫型功能评估。然后，将评估母体和胎儿免疫型在预测病例状态的影响。这项研究的结果将进一步违反影响免疫系统癌的免疫发育的关键特征。这些结果将有益于了解白血病的病因，并帮助儿童白血病的预测性和预防性方式，并为后续研究奠定了阶段，这些研究研究了研究产后因素，这些因素与先天性免疫免疫抑制结合在一起，以产生白血病。