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

Johns Hopkins University, Baltimore MD

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Abstract

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.