Dissertation/Thesis Abstract

Understanding the Impact of Hepatitis C Virus Infection and Cure on the Human Liver Immune System
by Doyle, Erin Heather, Ph.D., Icahn School of Medicine at Mount Sinai, 2019, 107; 22624293
Abstract (Summary)

Hepatitis C Virus (HCV) causes a unique infection within the liver. In more approximately 70% of people infected in causes a chronic disease that can lead to liver injury, inflammation, and eventually liver cancer or liver failure. This infection is marked by an intense immune response; HCV induces high levels of interferon-stimulated genes (ISG) and antigenic stimulation leading to T cell exhaustion. In the first project, we studied intrahepatic plasmacytoid dendritic cells (pDCs) in the context of a chronic HCV infection. Using cutting-edge approaches, e.g. CyTOF, multiplex cytokine analysis, etc., we showed that pDCs are not only still able to produce interferon alpha (IFNα) after TLR7/8 stimulation but produced more than matched PBMC counterparts. They were also highly polyfunctional, in the majority of cases making upwards of 3 cytokines/chemokines. In the second project, we examined what happens to the immune system, specifically T cells, when HCV is eradicated by direct acting antiviral drugs (DAAs). This is the first time in history that a chronic viral disease could be cured. Chronic antigenic stimulation causes PD-1 to be upregulated on HCV-specific T cells, but we found that PD-1 is elevated on bystander, non-HCV-specific T cells. This declines upon DAA therapy and subsequent cure. IFNα induces PD-1 on CD4 and CD8 T cells, which leads us to believe that it and the prolonged HCV stimulation both result in the upregulation of active, PD-1+ bystander T cells. These results, taken together, place IFNα in the center of an immunological web during chronic HCV infection and may be an important cytokine to target for future therapies.

Indexing (document details)
Advisor: Branch, Andrea D
Commitee: Alexandropoulos, Dina, Faith, Jeremiah, Homan, Dirk, Horowitz, Amir, Schwartz, Robert
School: Icahn School of Medicine at Mount Sinai
Department: Immunology
School Location: United States -- New York
Source: DAI-B 81/4(E), Dissertation Abstracts International
Subjects: Immunology
Keywords: HCV, Liver, PD1, pDCs
Publication Number: 22624293
ISBN: 9781687964892
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