Immunologic and Virologic Correlates of the Age-Related Decrease in HBV DNA in Children

儿童 HBV DNA 随年龄下降的免疫学和病毒学相关性

基本信息

批准号：
9528559
负责人：
KAREN F MURRAY
金额：
$ 45.72万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-30 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9528559
关键词：
10 year old 15 year old Adult Age Antigen-Antibody Complex Antigens Antiviral Therapy Biological Assay CCL2 gene CCL3 gene CXCL10 gene Cells Child Childhood Chronic Cirrhosis Clinical Clinical Trials Color Computer Simulation Cytometry Cytotoxic T-Lymphocyte-Associated Protein 4 DNA Data Data Set Enrollment Eotaxin FDA approved Funding Future Geographic Locations Goals Grant Granulocyte-Macrophage Colony-Stimulating Factor Hepatitis B Therapy Hepatitis B Virus IL8 gene Immune Immune Tolerance Immune response Immunologics Immunology Immunology procedure In Vitro Infection Interferon Type II Interleukin 2 Receptor Interleukin-1 Receptors Interleukin-10 Interleukin-13 Interleukin-15 Interleukin-17 Interleukin-2 Interleukin-4 Interleukin-5 Interleukin-6 Interleukin-7 Investigation Lead Liver Liver diseases Malignant neoplasm of liver Measures Methods Outcome Pacific Northwest Pathway interactions Patients Pattern Peptides Phenotype Positioning Attribute Primary carcinoma of the liver cells Principal Component Analysis Principal Investigator Public Health Risk Factors Role Route SLEB2 gene Serum Site Stains Structure T cell response T-Lymphocyte TNF gene Texas Universities Viral Virus Virus Diseases Voting Washington age effect age group age related austin base chemokine cohort cytokine fetal immune function improved insight lifetime risk novel organizational structure outreach patient subsets pressure public health relevance recruit response sex virology

项目摘要

DESCRIPTION (provided by applicant): Hepatitis B virus infection in children is an important public health problem, with the majority of children acquiring HBV via maternal-fetal acquisition, putting them at high lifetime risk (~25 - 50%) of cirrhosis and/or hepatocellular carcinoma (HCC). HBe Antigen (HBeAg) positivity and persistently high levels of HBV DNA are independent risk factors for cirrhosis and HCC in adults. While little is known about the immunologic response to HBV DNA in children, we have observed that older children in the HBRN have higher rates of HBeAg clearance and lower levels of HBV DNA compared to younger subjects. Thus, careful investigation of T cell responses to HBV antigens and cytokine/chemokine patterns in children of different ages may reveal immunologic determinants associated with viral clearance and lead to improved antiviral therapies in the future. The overarching goals of this application are two-fold: 1) Continue recruiting and enrolling children t the pediatric HBRN studies and retaining the 156 (pediatric cohort) and 31 immune tolerant (IT) subjects already enrolled by the Johns Hopkins Pediatric Clinical Center (pediatric liver centers at Johns Hopkins, UTSW and University of Washington 2) Characterize T cell immune phenotypes and responses to HBV antigens and cytokine chemokine patterns in HBV-infected children in 2 age groups 5 - 10 years vs 10 -18 years compared to age and sex-matched non-infected controls and existing T cell data in adults. The immune phenotype of T cells will be characterized by staining (multi-color FACS.) In vitro blockade of inhibitory pathways such as PD-1 and CTLA-4 to 'unmask' the underlying immune function in select patients will be explored. In the same patients and controls, the patterns of cytokines/chemokines will be assayed using LuminexTM (Austin, TX) apparatus and specific beadsets (Millipore, Billerica, MA): IL-1beta, IL-1 receptor antagonist, IL-2, soluble IL-2 receptor-alpha, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-13, IL-15, IL-17, IFN-gamma, IP-10, MIG, MIP-1alpha, MIP-1beta, MCP-1, GM-CSF, Eotaxin, and TNF-alpha. This immunological profile data will be analyzed using computational modeling, including Principal Component Analysis, hierarchical clustering, and network discovery methods; relationships between immune responses, HBeAntigen, and HBV DNA levels will be characterized. The significance of this project is to continue the productive contributions of the JHPCC to the pediatric studies of the HBRN and to contribute novel information regarding the effects of age on immune responses of children with HBV.

描述（由申请人提供）：儿童中的乙型肝炎病毒感染是一个重要的公共卫生问题，大多数儿童通过产妇获取获得HBV，使他们处于终身风险高（约25-50％）和/或肝细胞癌癌（HCC）。 HBE抗原（HBEAG）阳性和持续高水平的HBV DNA是成人肝硬化和HCC的独立危险因素。尽管对儿童的HBV DNA的免疫反应知之甚少，但我们观察到，与年轻受试者相比，HBRN中的大儿童的HBEAG清除率更高，HBV DNA水平较低。因此，对不同年龄段儿童中T细胞对HBV抗原和细胞因子/趋化因子模式的T细胞反应的仔细研究可能显示出与病毒清除率相关的免疫决定因素，并导致将来改善抗病毒疗法。该应用的总体目标是两个方面：1）继续招募和注册儿童，在儿科HBRN研究中，保留了156（小儿同伙）和31名免疫耐受性（IT）受试者（IT）受试者（IT）已经由Johns Hopkins Pediotial Clinical Clinical Centric Centric Centric Centric Centrial Centrip and Simplys and Simply tarement and Simplys Simplys Simplys Simplys Simplys Simplys Simply tarement of Johns Hopkins Pediotic Clinatial Centric Centers（IT）。与年龄和性别匹配的未感染对照组相比，2岁年龄组5-10岁的HBV抗原和细胞因子趋化因子模式与10 -18岁的儿童相比，成年人的现有T细胞数据。 T细胞的免疫表型将以染色（多色FACS）在体外阻断抑制性途径（例如PD-1和CTLA-4）的体外阻断，以“揭示”选定患者中的潜在免疫功能。在同一患者和对照组中，将使用Luminextm（Austin，TX）设备和特定珠子（Millipore，Billerica，MA）测定细胞因子/趋化因子的模式：IL-1Beta，IL-1受体拮抗剂，IL-2 IL-10，IL-13，IL-15，IL-17，IFN-GAMMA，IP-10，MIG，MIP-1ALPHA，MIP-1BETA，MCP-1，GM-CSF，EOTAXIN，EOTAXIN，EOTAXIN和TNF-ALPHA。将使用计算建模（包括主成分分析，层次聚类和网络发现方法）分析此免疫概况数据；免疫反应，Hbeantigen和HBV DNA水平之间的关系将被表征。该项目的意义是继续JHPCC对HBRN的儿科研究的生产贡献，并为年龄对HBV儿童免疫反应的影响提供新的信息。