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：
8974909
负责人：
KAREN F MURRAY
金额：
$ 39.05万
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/8974909
关键词：
10 year old 15 year old Adult Age Antigens Antiviral Therapy Biological Assay CCL2 gene CXCL10 gene Cells Chemokine (C-C Motif) Ligand 4 Child Childhood Cirrhosis Clinical Clinical Trials Color Complex Computer Simulation Cytometry DNA Data Data Set Enrollment Eotaxin FDA approved Funding Future Geographic Locations Goals Grant Granulocyte-Macrophage Colony-Stimulating Factor Hepatitis B Virus IL8 gene Immune Immune response Immunologics Immunology In Vitro Infection Interferon Type II Interleukin-1 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 Pb clearance Peptides Phenotype Positioning Attribute Primary carcinoma of the liver cells Principal Component Analysis Principal Investigator Public Health Recruitment Activity Risk Factors Role Route Serum Site Small Inducible Cytokine A3 Staining method Stains Structure Subgroup T cell response T-Lymphocyte Texas Tumor Necrosis Factor-alpha Universities Viral Virus Virus Diseases Voting Washington age effect age group age related austin base chemokine cohort cytokine fetal human TNF protein immune function improved insight lifetime risk novel organizational structure outreach pressure public health relevance receptor response sex

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%） 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，但人们对此知之甚少。儿童对 HBV DNA 的免疫反应，我们观察到 HBRN 中年龄较大的儿童与年轻受试者相比，HBeAg 清除率较高，而 HBV DNA 水平较低，因此，需要仔细研究 T 细胞对 HBV 抗原和细胞因子/趋化因子模式的反应。不同年龄儿童的免疫学决定因素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。该应用的总体目标有两个：1）继续招募和入组儿科 HBRN。研究并保留约翰·霍普金斯儿科临床中心（约翰·霍普金斯大学、UTSW 和华盛顿大学的儿科肝脏中心 2）已入组的 156 名（儿科队列）和 31 名免疫耐受 (IT) 受试者，表征 T 细胞免疫表型和对 HBV 的反应与年龄和性别匹配的 2 个年龄组 5 - 10 岁与 10 -18 岁的 HBV 感染儿童的抗原和细胞因子趋化因子模式相比未感染的对照和成人中现有的 T 细胞数据将通过染色（多色 FACS）来表征。体外阻断 PD-1 和 CTLA-4 等抑制途径以“揭露”T 细胞的免疫表型。将探索选定患者的潜在免疫功能。在相同的患者和对照中，将使用 LuminexTM（奥斯汀，德克萨斯州）仪器和特定珠组（Millipore，Billerica， MA)：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、嗜酸细胞趋化因子和 TNF -α。将使用计算模型来分析该免疫学特征数据，包括主成分分析、层次聚类和免疫反应、HBe抗原和 HBV DNA 水平之间的网络发现方法；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。