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: 9132692
• 负责人: Xiaomei Ma
• 金额: $ 61.85万
• 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/9132692
• 关键词: 14 year old; Acute Lymphocytic Leukemia; Affect; Age; Archives; B-Cell Acute Lymphoblastic Leukemia; B-Lymphocytes; Birth; Blood; Blood specimen; 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; FOXP3 gene; Fetal Tissues; Fetus; Genetic; Genotype; HLA Antigens; Habitual Abortion; Health; 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; Modality; Modeling; Mothers; Natural Killer Cells; Neonatal; Newborn Infant; Outcome; Pathway interactions; Pattern; Perinatal; Phenotype; Physicians; Placenta; Play; Pregnancy; Regulatory T-Lymphocyte; Research; Research Project Grants; Risk; Risk Factors; Series; Serological; Siblings; Spottings; Staging; Testing; Visit; base; case control; cytokine; developmental genetics; epidemiology study; fetal; follow-up; immune function; killer immunoglobulin-like receptor; leukemia; maternal serum; neonate; postnatal; 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（由申请人提供）：儿童白血病是最常见的儿童癌症，但在绝大多数情况下，该疾病的病因尚不清楚。流行病学研究指出，感染模式是白血病的重要危险因素——接触各种不同数量的儿童接触者（例如日托所和年长的兄弟姐妹）对白血病有保护作用。这些关联对于白血病的前 B 细胞免疫表型最为强烈，我们将在此进行研究。新的流行病学证据表明，对感染的强烈反应（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缺乏免疫抑制细胞因子 IL10，这意味着他们在出生时就带有先天性免疫畸变。根据这些观察结果，我们假设新生儿免疫功能的特征（即缺乏免疫抑制）对于前 B 细胞急性淋巴细胞白血病 (pre-B ALL) 的风险很重要。在当前的研究中，我们将进一步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。我们将收集一系列 500 名 ALL 病例儿童及其母亲，以及 500 名对照者及其母亲，以评估对母亲体内胎儿形成支持性免疫环境至关重要的两种遗传因素（HLA-C 和 KIR）是否会影响胎儿免疫状态和白血病病例/对照状态。我们还将利用 200 名病例母亲和 500 名对照母亲来评估新生儿免疫功能表型是否受到妊娠期间母体免疫状态的影响。除了 IL10 水平之外，我们还将通过其他标记来定义胎儿免疫表型，包括 TGF-β、IFN-β 和 T 调节细胞标记（关键转录因子 FOXP3 的差异甲基化区域）。首先将评估母体细胞因子和 IGE 水平以及 KIR 基因型（以及新生儿的 HLA-C 基因型）对对照新生儿免疫功能的影响。然后将评估母体和胎儿免疫表型对预测病例状态的影响。这项研究的结果将进一步否定影响免疫系统癌症的免疫发育的关键特征。这些结果将有利于了解白血病的病因，并有助于儿童白血病的预测和预防方式，并为后续研究奠定基础，以检查与先天性免疫抑制相结合产生白血病的产后因素。