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

• 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
• 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

 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(申请人提供)：儿童中的乙肝病毒感染是一个重要的公共卫生问题，大多数儿童通过母婴接触感染乙肝病毒，使他们面临患上肝硬变和/或肝细胞癌的高风险(约25%-50%)。HBe抗原(HBeAg)阳性和HBVDNA持续高水平是成人肝硬变和肝癌的独立危险因素。虽然对儿童对HBVDNA的免疫应答知之甚少，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HBVDNA水平较低。因此，仔细研究不同年龄段儿童对乙肝病毒抗原的T细胞反应和细胞因子/趋化因子模式，可能会揭示与病毒清除相关的免疫学决定因素，并在未来改进抗病毒治疗。该应用程序的总体目标有两重：1)继续招募和招募儿童参加HBRN儿科研究，并保留约翰霍普金斯大学儿科临床中心(约翰霍普金斯大学、德克萨斯大学和华盛顿大学2的儿科肝脏中心)已经登记的156名(儿科队列)和31名免疫耐受(IT)受试者，比较年龄和性别匹配的非感染对照组和现有的成人T细胞数据，分析5-10岁和10-18岁两个年龄组的乙肝病毒感染儿童的T细胞免疫表型和对乙肝病毒抗原和细胞因子趋化因子的应答模式。T细胞的免疫表型将通过染色(多色FACS)来表征。在体外，将探索阻断PD-1和CTLA-4等抑制通路，以揭示选定患者的潜在免疫功能。在相同的患者和对照组中，细胞因子/趋化因子的模式将使用LumenexTM(奥斯汀，TX)设备和特定的珠组(Milliporle，Billerica，MA)进行检测：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、干扰素-γ、IP-10、MIG、MIP-1α、MIP-1β、MCP-1、GM-CSF、嗜酸性粒细胞集落刺激因子和肿瘤坏死因子-α。这些免疫图谱数据将使用计算建模进行分析，包括主成分分析、层次聚类和网络发现方法；免疫应答、HBe抗原和HBVDNA水平之间的关系将被表征。该项目的意义在于继续发挥JHPCC对HBRN儿科研究的建设性贡献，并为年龄对乙肝病毒携带者儿童免疫反应的影响提供新的信息。