Impact of low IL-10 levels at birth and leukemia risk

出生时 IL-10 水平低和白血病风险的影响

• 批准号: 8674581
• 负责人: SCOTT C. KOGAN
• 金额: $ 66.69万
• 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: 2014-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8674581
• 关键词: Acceleration; Acute Lymphocytic Leukemia; Affect; Age; Animal Model; Animals; Antigens; Archives; B-Lymphocytes; Biological Assay; Birth; Birth Order; Blood; California; Caring; Cells; Child; Childhood; Childhood Acute Lymphocytic Leukemia; Childhood Acute Myeloid Leukemia; Childhood Leukemia; Clinical; Contracts; Databases; Defect; Development; Diagnosis; Disease; ETV6 gene; Ensure; Epidemiologic Studies; Epidemiology; Etiology; Exposure to; Face; Family; Goals; Grant; Health; Hereditary Disease; Human; Immune; Immune response; Immune system; Immunosuppressive Agents; Incidence; Individual; Infection; Infectious Agent; Interleukin-10; Interview; Knockout Mice; Life; Link; Malignant Neoplasms; Measures; Mediator of activation protein; Medical; Medical Records; Modeling; Mus; Mutation; Myelogenous; Neonatal; Newborn Infant; Partner in relationship; Pathway interactions; Patients; Pattern; Physicians; Prevention strategy; Property; Proteins; RUNX1 gene; Reporting; Resources; Risk; Risk Factors; Role; Sampling; Severities; Siblings; Spottings; Stimulus; Survivors; Symptoms; Systems Development; Testing; United States; Vulnerable Populations; Work; base; blood resource; cancer type; cytokine; early childhood; effective therapy; epidemiology study; experience; immunopathology; improved; knowledge base; leukemia; leukemogenesis; mouse model; novel; protective effect; public health relevance; research study; response; vector

DESCRIPTION (provided by applicant): Acute Leukemia (Lymphoblastic and Myeloid, ALL and AML) is the most common type of cancer in children (age 0-14 years), but the causes of the disease are uncertain in the vast majority of cases. As leukemia is a cancer of the immune system, its risk is profoundly affected by patterns of infections. Epidemiology studies have shown that exposure to a wide variety and number of childhood contacts (e.g., daycare attendance and older siblings) are protective against childhood ALL. More recent epidemiologic evidence, however, suggests that vigorous response to infectious agents, as measured by infections that require care from medical professionals, is a risk factor for both childhood ALL and AML. Additionally, in our studies we found that ALL cases had decreased levels of the immunosuppressive cytokine IL-10 at birth when compared to control children, suggesting that they enter the world with a congenital immune aberration. In the current proposal, we wish to develop these two critical observations (low IL-10, more severe childhood infections) into a connected and recognizable causal pathway, using both epidemiologic observation in humans, and a manipulable mouse model. In Aim 1, we will measure IL-10 levels in 260 case and 390 control children's archived neonatal dried blood spots (DBS) collected at birth and stored for all California children, and perform association analyses between the IL-10 levels and physician diagnosed infections after birth and before leukemia diagnosis. This aim will be completed using two unique resources: (i) the California Genetic Diseases Branch archived newborn blood resource, which store DBS samples from all California-born children, and (ii), the Kaiser Permanente Northern California medical record database. We will perform this analysis in both children who contracted leukemia and those who did not, to determine whether infections are an obligate intermediary between IL-10 levels and risk of leukemia. In Aim 2, we will use a mouse model that recapitulates the most common subtype of childhood leukemia, those with ETV6-RUNX1 (TEL-AML1) translocations, to study this same causal pathway. ETV6-RUNX1-carrying mice will be mated with IL-10 knockout mice, yielding a new strain that has lower IL-10 at birth along with a pre-leukemic mutation, directly mirroring the human situation. These mice will be challenged with immune stimuli to test the putative cooperative effect of infection with these two pre-leukemic attributes. The animals will be assayed following the challenge to ascertain the interactive effects of the pre-leukemic mutation, IL-10 levels, and immune challenge on the expansion of pre-leukemic immature B-cells and on leukemogenesis. The use of this mouse model will inform and be informed by epidemiologic observations, permitting the construction of a synergistic knowledge base on a new leukemia causal hypothesis within the proposed five year grant period.

描述（由申请人提供）：急性白血病（淋巴细胞和髓样，全部和AML）是儿童中最常见的癌症类型（0-14岁），但在绝大多数病例中，疾病的原因尚不确定。由于白血病是免疫系统的癌症，因此其风险受感染模式的深刻影响。流行病学研究表明，暴露于各种各样的童年接触（例如，日托出勤率和较老的兄弟姐妹）对童年时期都有保护。然而，最近的流行病学证据表明，通过需要医疗专业人员护理的感染衡量的感染因素对感染者的剧烈反应是儿童时期和AML的危险因素。此外，在我们的研究中，我们发现与对照儿童相比，所有病例在出生时出生时的免疫抑制性细胞因子IL-10水平降低，这表明他们以先天性免疫像差进入世界。在当前的提案中，我们希望使用人类的流行病学观察和可操纵的小鼠模型，将这两个关键观察结果（低IL-10，更严重的儿童感染）发展为可互联且可识别的因果途径。在AIM 1中，我们将在260例病例中测量IL-10水平和390个对照儿童在出生时收集并为所有加利福尼亚儿童存储的儿童存档的新生儿干燥血液点（DB），并在出生后和白血病诊断前诊断出感染的IL-10水平和医生之间进行了关联分析。这个目标将使用两个独特的资源完成：（i）加利福尼亚遗传疾病分支存档的新生儿资源，这些血液资源存储了所有加利福尼亚儿童的DBS样本，以及（ii），Kaiser Permanente Northerente北加州病历数据库。我们将对同性白血病和没有患有白血病的孩子进行此分析，以确定感染是否是IL-10水平和白血病风险之间的专有中介。在AIM 2中，我们将使用一个小鼠模型，该模型概括了儿童白血病最常见的亚型，那些具有ETV6-RUNX1（Tel-AML1）易位的小鼠模型来研究同样的因果途径。 ETV6-携带的小鼠将与IL-10基因敲除小鼠配对，产生一种新的菌株，该菌株在出生时与leukepication突变同时具有较低的IL-10，直接反映了人类状况。这些小鼠将受到免疫刺激的挑战，以测试这两种美食前属性感染的推定合作作用。在挑战之后，将对这些动物进行测定，以确定白血病前突变，IL-10水平以及免疫挑战对膨胀前未成熟B细胞和白血病发生的挑战的互动效应。该小鼠模型的使用将通过流行病学观察来告知和告知，从而允许在拟议的五年赠款期内建立在新的白血病因果假设上的协同知识基础。