Liver cytokine profiles during hepatitis C virus infection
(Crawford, Liu, Svetlov & Davis).

The objective of this project is to define the role of cytokines in recovery versus disease progression following infection by hepatitis C virus (HCV), based on the premise that cytokines produced by lymphocytes, hepatocytes, and other cell types in the infected liver may play a central role in modulating the course of hepatitis C virus infection. For this purpose, we have available a unique collection of frozen liver tissue samples from patients with HCV infection, including post-liver transplant patients with re-infected liver grafts. We hypothesize that tissue cytokine expression patterns determine the clinical course of hepatitis C viral infection, and hence, liver cytokine expression patterns may predict the development of liver cirrhosis. This hypothesis will be tested by determining the cytokine mRNA expression profiles in liver biopsy tissues of hepatitis C patients and in HCV positive cirrhotic liver diseases. The rationale for this approach is that cytokines appear to play a direct role in elimination of many non-cytopathic virus infections, particularly those by RNA viruses. The functional roles of cytokines during hepatitis C infection are not completely known, but several lines of evidence have heightened interest. In particular, cytotoxic T lymphocytes (CTL), which are known to be correlated with viral clearance, are influenced by a number of immunomodulatory cytokines. CTL can secrete IFN and other cytokines, producing a wide spectrum of pro-inflammatory events. Simultaneously, cytokines can stimulate hepatocyte regeneration and fibroblast proliferation, leading to cirrhosis if the process persists. Apoptotic cells (both hepatocytes and inflammatory cells) are noted in HCV-infected livers, but their role in hepatitis pathogenesis is not defined. As a therapeutic agent, interferon alpha may induce viral clearance by regulating cytokine gene expression, and hence the immune response. It is evident that delineation of the expression of tissue cytokines is central to understanding the pathogenesis of liver injury, and potential recovery, during hepatitis C viral infection. These studies will be done with our immune subarray, which will cover, in addition to other genes, approximately 300 adhesion molecules, integrins, cytokines, chemokines, interleukins, the TGF superfamily, the TNF superfamily, fibroblast growth factors and angiogenic factors. Liver biopsy tissues are archived fresh frozen tissues collected in our institution. Control tissues are collected from normal liver donor biopsies. The samples will be divided into several groups according to the clinical status, including acute infection (especially in the reinfected liver graft), chronic infection (in both liver graft and native liver community-acquired HCV), chronic infection with response to IFN alpha, chronic infection without response to IFN alpha, chronic infection with initial IFN alpha response and then relapse, and normal controls. Resected cirrhotic liver tissues are routinely available during liver explantation, and corresponding clinical information excluding patient identity will be available. The control liver tissue will be noncirrhotic liver tissues resected for metastatic tumors. Companion liver tissue will be examined histologically, especially to verify normality in the controls. Correlation between expression patterns and the clinical parameters will be analyzed. Of particular interest is the clinical behavior of HCV infection as a function of the expressed cytokines and other immuno-regulatory molecules. Specific attention will be given to comparing the known biology of cytokines expressed in HCV-infected tissues with the clinical outcome of each patient group. This study will provide critical information on the behavior of cytokines during ongoing HCV infection, and may provide key insights into the pathogenesis of chronic disease. Conversely, the information generated from this study will aid in the identification of cytokines that directly inhibit HCV replication and cytokines that directly induce infected hepatocytes to undergo apoptosis, projects which are ongoing in our laboratory. This latter information may enable the development of much more effective therapies for chronic HCV infection. Third, our data will provide a foundation for using cytokine array technology for patient management.

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