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，大多数儿童通过母胎感染乙型肝炎病毒，使他们一生面临肝硬化和/或肝硬化的高风险（约 25 - 50%）或肝细胞癌（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。虽然我们对儿童对 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 中年龄较大的儿童 HBeAg 清除率较高，而 HBV DNA 水平较低。因此，仔细研究不同年龄儿童的 T 细胞对 HBV 抗原的反应和细胞因子/趋化因子模式可能会揭示与病毒清除相关的免疫决定因素，并导致未来抗病毒治疗的改进。该申请的总体目标有两个：1) 继续招募和入组儿童参加儿科 HBRN 研究，并保留约翰·霍普金斯儿科临床中心（儿科队列）已入组的 156 名（儿科队列）和 31 名免疫耐受 (IT) 受试者。约翰·霍普金斯大学、UTSW 和华盛顿大学的肝脏中心 2) 表征 T 细胞免疫表型以及对 HBV 抗原和细胞因子趋化因子模式的反应与年龄和性别匹配的未感染对照以及成人现有 T 细胞数据相比，2 个年龄组（5 - 10 岁与 10 -18 岁）的 HBV 感染儿童中的结果。 T 细胞的免疫表型将通过染色（多色 FACS）来表征。将探索体外阻断 PD-1 和 CTLA-4 等抑制途径，以“揭示”选定患者的潜在免疫功能。在相同的患者和对照中，细胞因子/趋化因子的模式将使用 LuminexTM（奥斯汀，德克萨斯州）仪器和特定珠组（密理博，比尔里卡，马萨诸塞州）进行测定：IL-1β、IL-1 受体拮抗剂、IL-2、可溶性IL-2 受体-α、IL-4、IL-5、IL-6、IL-7、IL-8、IL-10、IL-13、IL-15、IL-17、 IFN-γ、IP-10、MIG、MIP-1α、MIP-1β、MCP-1、GM-CSF、嗜酸细胞活化趋化因子和 TNF-α。该免疫学特征数据将使用计算模型进行分析，包括主成分分析、层次聚类和网络发现方法；免疫反应、HBe抗原和 HBV DNA 水平之间的关系将得到表征。该项目的意义在于继续 JHPCC 对 HBRN 儿科研究的富有成效的贡献，并提供有关年龄对 HBV 儿童免疫反应影响的新信息。