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.