Effect of early diet and virus infections on immune regulation and the development islet autoimmunity -Trial to Reduce IDDM in the Genetically at Risk (TRIGR)

早期饮食和病毒感染对免疫调节和胰岛自身免疫发育的影响 - 减少遗传风险 (TRIGR) 中 IDDM 的试验

• 批准号: 8970936
• 负责人: Suvi Mirjami Virtanen
• 金额: $ 109.58万
• 依托单位: NATIONAL INSTITUTE FOR HEALTH & WELFARE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-10 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8970936
• 关键词: 10 year old; Address; Affect; Age; Antibodies; Antiviral Agents; Attenuated; Autoantibodies; Autoimmunity; Biological Assay; Blood specimen; Breast Feeding; Caseins; Cattle; Cells; Child; Childhood; Collection; Cost Analysis; Country; Coxsackie B Viruses; Data Collection; Development; Diabetes Mellitus; Diet; Dietary Factors; Dietary Intervention; Dietary Proteins; Disease susceptibility; Double-Blind Method; Enterovirus; Enterovirus Infections; Enzyme-Linked Immunosorbent Assay; Enzymes; Epigenetic Process; Etiology; Exposure to; Fatty Acid Desaturases; Fatty Acids; Fatty acid glycerol esters; First Degree Relative; Freezing; Gas Chromatography; Genes; Genetic; Genetic Polymorphism; Health; Hereditary Disease; Human; Immune; Immune Response Genes; Immune response; Immunity; Immunization; Immunoassay; Infant; Inflammation; Insulin; Insulin-Dependent Diabetes Mellitus; Intake; Integration Host Factors; Interferon Type II; Interleukin-13; Interleukin-17; Interleukin-2; Interleukin-4; Interleukin-5; International; Intestines; Islets of Langerhans; Laboratories; Lactation; Measures; Mediating; Metabolism; Methodology; Methods; Milk; Milk Proteins; Modification; Mothers; Nutritional; Omega-3 Fatty Acids; Participant; Pathogenesis; Peripheral Blood Mononuclear Cell; Permeability; Play; Radio; Radioactive; Randomized Clinical Trials; Recruitment Activity; Regulation; Regulatory T-Lymphocyte; Risk; Risk Factors; Role; Sampling; Serum; Tissues; Viral; Virus; Virus Diseases; Vitamin D; base; case control; chemokine; cohort; cytokine; design; endocrine pancreas development; follow-up; improved; infancy; inflammatory marker; interleukin-22; islet; oral tolerance; response; sample collection

DESCRIPTION (provided by applicant): Effect of early diet and virus infections on immune regulation and the development islet autoimmunity -Trial to Reduce IDDM in the Genetically at Risk (TRIGR). The study will yield important new information about the main environmental candidate risk factors in the pathogenesis of type 1 diabetes (T1D) utilizing the setup of TRIGR (dietary intervention). The aim is to evaluate associations between n-3 fatty acids, vitamin D, cow's milk exposure and viral infections with indicators of immune regulation and inflammation as well as induction of islet autoimmunity. Islet autoimmunity is defined as repeated positivity fo at least two diabetes-associated autoantibodies out of four ones measured. The current study will be based on biosamples collected in the TRIGR cohort. TRIGR study is an international double-blind randomized clinical trial of 2159 infants with HLA-conferred disease susceptibility and a first-degree relative with T1D recruited between 2002-2007 in 15 countries. In TRIGR an extensively hydrolyzed casein formula is compared to regular cow's milk based one. All subjects are followed until the youngest child will be 10-year-old. Blood samples are collected at 3 to 12 months' intervals. We measure from serum in cohort or nested case-control design: fatty acid composition with gas chromatography; 25-OH-vitamin D concentration with chemiluminescent mircoparticle immunoassay; virus antibodies with plaque neutralization and enzyme immune assay; cow's milk antibodies with enzyme-linked immunosorbent assay; antibodies to dietary bovine insulin by using the competitive radio-immunoassay with radioactive and cold insulin; and cytokines and chemokines with the Milliplex MAP kit. When studying cell-mediated responses to Coxsackievirus B, ß-lactoglobulin and bovine insulin, we use frozen peripheral blood mononuclear cells (PBMC), from which we measure Treg Th1, Th2 and Th17 markers, FoxP3, CTLA-4, IFN-g, IL-4, IL-5, IL-13, IL-17 and IL-22, using RT-qPCR methodology in cow's milk protein stimulated PBMCs. We will also analyze from frozen PBMCs the epigenetic modulation of two genes (FOXP3, IL-2) responsible for the development of regulatory T-cells. The methods are very well established and well-functioning in our laboratories. The analysis can start straight after the samples are received from TRIGR. This application covers the costs for the analysis of serum 25-OH-vitamin D concentration, serum fatty acids, immune regulation, inflammatory markers, and virus infections. It also covers coordination, data collection, management and statistical analysis as well as sample collection and aliquation for the current study.

描述（由申请人提供）：早期饮食和病毒感染对免疫调节和胰岛自身免疫发育的影响 - 减少遗传风险中 IDDM 的试验（TRIGR）。该研究将利用 TRIGR（饮食干预）的设置，得出有关 1 型糖尿病 (T1D) 发病机制的主要环境候选危险因素的重要新信息。目的是评估 n-3 脂肪酸、维生素 D、牛奶暴露和病毒感染与免疫调节和炎症指标以及胰岛自身免疫诱导之间的关系。胰岛自身免疫被定义为测量的四种与糖尿病相关的自身抗体中至少两种重复呈阳性。 目前的研究将基于 TRIGR 队列中收集的生物样本。 TRIGR研究是一项国际双盲随机临床试验，2002年至2007年间在15个国家招募了2159名具有HLA赋予疾病易感性的婴儿和一名患有T1D的一级亲属。在 TRIGR 中，将深度水解酪蛋白配方与普通牛奶配方进行比较。所有科目都会被跟踪直至最小的孩子 10 岁。每隔 3 至 12 个月采集一次血样。 我们通过队列或巢式病例对照设计来测量血清：用气相色谱法测量脂肪酸组成；化学发光微粒免疫测定法测定 25-OH-维生素 D 浓度；具有噬菌斑中和和酶免疫测定的病毒抗体；采用酶联免疫吸附测定法检测牛奶抗体；通过使用放射性和冷胰岛素的竞争性放射免疫测定法来获得膳食牛胰岛素的抗体；使用 Milliplex MAP 试剂盒检测细胞因子和趋化因子。在研究细胞介导的对柯萨奇病毒 B、β-乳球蛋白和牛胰岛素的反应时，我们使用冷冻外周血单核细胞 (PBMC)，从中测量 Treg Th1、Th2 和 Th17 标记物、FoxP3、CTLA-4、IFN-g、IL-4、IL-5、IL-13、IL-17 和 IL-22，使用 牛奶蛋白刺激的 PBMC 中的 RT-qPCR 方法。我们还将分析冷冻 PBMC 中负责调节性 T 细胞发育的两个基因（FOXP3、IL-2）的表观遗传调节。这些方法在我们的实验室中已经非常成熟并且运行良好。从 TRIGR 收到样品后即可立即开始分析。 该应用涵盖了血清 25-OH-维生素 D 浓度、血清脂肪酸、免疫调节、炎症标志物和病毒感染分析的费用。它还涵盖协调、数据收集、管理和统计分析以及当前研究的样本收集和分配。

项目成果

Associations Between Serum Fatty Acids and Immunological Markers in Children Developing Islet Autoimmunity-The TRIGR Nested Case-Control Study.

• DOI: 10.3389/fimmu.2022.858875
• 发表时间: 2022
• 期刊: Frontiers in immunology
• 影响因子: 7.3