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American Liver Foundation
39 Broadway, Suite 2700
New York, New York 10006
Herman Lopata Memorial Hepatitis Postdoctoral Research Fellowship
Project Title: Liver dendritic cell recruitment and differentiation during chronic HCV infection
Eighty percent of individuals infected with HCV fail to clear their infection on their own, largely as the result of weak, narrowly targeting or waning antiviral T cell responses. One possibility is that the observed defects in HCV immunity are a direct result of inefficient T cell priming by professional antigen presenting cells (APCs). Unfortunately, progress in understanding potential defects in antigen presentation during chronic HCV infection has been impeded by the lack of a small animal model in which to study the host response. Using a large cohort of patients undergoing liver transplantation for chronic HCV infection and non HCV-related liver disease, Dr. Best has observed that a number of professional APCs, including dendritic cells (DCs), reside within the human liver microenvironment
that have the potential to shape HCV-specific immunity. Among six identified populations of liver APCs, a novel population of CD34+ myeloid ”progenitors” was also discovered. Interestingly, chronic HCV infection was characterized by a drastic reduction in the frequency of “progenitor” cells and a significant increase in the frequency of intrahepatic myeloid DCs. Moreover, intrahepatic myeloid DCs revealed the HCV-induced expression of numerous maturation markers, including CD80, CD83, CD40 and PD-L1, and were responsive to antigenic stimulation in vitro through the secretion of IL-12. Using various immunological techniques developed by her laboratory, Dr. Best proposes to test the hypothesis that the chronic HCV liver microenvironment promotes the differentiation of myeloid liver DCs, and that these DCs regulate HCV-specific T cell responses through B7-mediated pathways and the secretion of effector cytokines. Phenotypic analysis of liver “progenitor” cells, and the use of in vitro and in vivo stem cell differentiation assays also allow Dr. Best to determine the recruitment and DC differentiation fate of these cells during chronic HCV infection. Comparisons of immunomodulatory receptor expression, cytokine secretion potential and antigen presenting capacity of mature liver APCs from uninfected and HCV-infected patients will allow Dr. Best to identify mechanisms of immune system modulation by these cells in the context of chronic HCV infection. Together, the experiments proposed will reveal potential mechanisms underlying HCV chronicity, and will serve useful for the development of novel therapeutic strategies.
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