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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.
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 |
Source Type: | DISSERTATION |
Subjects: | Immunology |
Keywords: | HCV, Liver, PD1, pDCs |
Publication Number: | 22624293 |
ISBN: | 9781687964892 |