Browsing Electronic Theses and Dissertations by Author "Aguilar-valenzuela, Renan A"
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ItemImmunomodulation in Adenovirus-Induced Viral HepatitisAguilar-valenzuela, Renan A; Sun, Jiaren; Soong, Lynn; Yi, MinKyung; Lai, Laijung; Melby, PeterMany viruses can infect the liver and persist there as their site of primary infection. The clinical outcomes in viral hepatitis can range from complete pathogen clearance and recovery of liver function to failure to contain the infection and loss of liver function. Because hepatotropic viruses are one of the major etiologic causes of morbidity and mortality worldwide, there is great interest in examining the mechanisms of viral clearance versus persistence. Immune modulation with interleukin 33 (IL-33) and hepatocytes growth factor (HGF) have great potential for developing therapeutic strategies. The liver produces and releases IL-33 and HGF upon viral infection, two molecules that favor hepatocyte survival by up-regulating bcl-2 gene, which have also immune regulatory functions. Here, we asked whether these pro-survival and regulatory molecules could influence outcomes in virally induced hepatitis. By using an animal model of adenovirus (Ad)-induced hepatitis and in vitro studies, we explored the immune effects of these two hepatocyte survival factors and also their effects on the hepatic immune response. Project I focused on the role of IL-33. We measured its expression and serum concentration during the course of viral hepatitis. We found that IL-33, along with its receptor (ST-2), is expressed during the course of Ad-induced hepatitis. To examine IL-33’s immunologic role, we administered exogenous IL-33 during the course of infection, which was found to decrease hepatocytes apoptosis and ALT release by inhibiting TNF- production. However, lymphocyte infiltration was not modified by IL-33. Interestingly, IL-33 enhanced both type 1 cytokines (IL-2 and IFN- and type 2 cytokines (IL-5 and IL-13). In addition, we found that exogenous IL-33 promoted the expansion of ILC2 (nuocytes), a recently described immune cell type whose lineage is negative and produces Th2 cytokines. Thus, we examined whether ILC2 lead to the immune protection exerted by IL-33 in viral hepatitis. When we co-cultured ILC2 with intrahepatic lymphocytes from Ad-infected mice, TNF- production was decreased. Collectively, this study indicates that IL-33 could be explored as a promising therapeutic tool in viral hepatitis. Project II focused on the role of HGF, a pleiotropic cytokine known to be related with cell survival and proliferation. In this project, we provided evidence that HGF axis is activated during viral hepatitis. We further examined its role during viral hepatitis by over-expressing the hgf gene and found that exogenous HGF ameliorated liver damage by diminishing lymphocyte infiltration. In addition, HGF also decreases the expression of type I interferon and IL-6. To examine the effects of HGF on DC activation in vivo, we measured IL-12p40 and CD40 expression and found that both molecules decreased in the presence of HGF. In addition, studies involving bone marrow-derived DC confirmed our findings in vivo. To further characterize HGF’s role in immune function, we examined T cell activation and found that HGF promotes a partially activated T cell phenotype (CD44hiCD62Lhi). We also observed that HGF diminished TGF- and IL-10 production in serum and liver tissues. In line with these results, the expression of CD8 T cell inhibitory markers (Tim-3 and PD-1) also decreased. Our findings suggest to us that HGF mediates organ protection by promoting hepatocyte survival, but like IL-33, it does not abolish viral clearance. In summary we have described the hepatoprotective and immune-regulatory role of IL-33 and HGF in Ad-induced hepatitis. Furthermore, these two naturally occurring molecules in the liver do not mediate liver protection by abolishing anti-viral responses. Therefore, immune regulation with both cytokines could be a promising therapeutic tool to treat viral hepatitis.