BACKGROUND & AIMS T-helper (Th)17 cells that secrete interleukin (IL)-22 have immunomodulatory and protective properties in the liver and other tissues. IL-22 induces expression of proinflammatory genes, but is also mitogenic and anti-apoptotic in hepatocytes. Therefore, it could have multiple functions in the immune response to hepatitis B virus (HBV). METHODS We examined the role of IL-22 in regulating liver inflammation in HBV transgenic mice and measured levels of IL-22 in HBV-infected patients. RESULTS In HBV transgenic mice, injection of a single dose of IL-22 increased hepatic expression of proinflammatory genes, but did not directly inhibit virus replication. When splenocytes from HBV-immunized mice were transferred into HBV transgenic mice, the severity of the subsequent liver damage was ameliorated by neutralization of IL-22. In this model, IL-22 depletion did not affect interferon-γ–mediated noncytopathic inhibition of virus replication initiated by HBV-specific cytotoxic T cells, but it significantly inhibited recruitment of antigen–non-specific inflammatory cells into the liver. In patients with acute HBV infections, the percentage of Th17 cells in peripheral blood and concentration of IL-22 in serum were significantly increased. CONCLUSION IL-22 appears to be an important mediator of the inflammatory response following recognition of HBV by T cells in the liver. These findings might be relevant to the development of cytokine-based therapies for patients with HBV infection.
Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection affect >500 million people worldwide and are significant causes of liver cirrhosis and hepatocellular carcinoma. The pathogenesis of HBV and HCV infection can vary widely with respect to the outcome of initial infection to self-resolving acute or chronic disease, the extent of viremia and liver inflammation during chronic infection, and the eventual development of liver cirrhosis and hepatocellular carcinoma. The host immune response is an important factor in the variable consequences of these infections, because the innate and adaptive intrahepatic antiviral responses are an intricate balance of immune effector cells and cytokines that control virus replication but can also cause liver damage. IL-22 is an important cytokine that plays a pleiotropic protective, but sometimes also pathological, role in several tissues/organs, including the liver. Therefore, IL-22 is likely to be an important factor in the pathogenesis and clinical outcome of HBV and HCV infection. However, the precise beneficial, and possible detrimental, effects of this cytokine may vary among different disease states that are associated with distinct inflammatory microenvironments. This review summarizes our understanding of the protective and pathological activities of IL-22, with an emphasis on the liver, and discusses the implications of these effects as they relate to viral hepatitis.
As one of the world's most common infectious diseases, hepatitis B virus (HBV) is a serious worldwide public health problem, with HBV-associated liver disease accounting for more than half a million deaths each year. Although there is an effective prophylactic vaccine currently available to prevent infection, it has a number of characteristics that are suboptimal: multiple doses are needed to induce long-lasting immunity, immunity declines over time, it does not elicit protection in some individuals, and it is not effective therapeutically. We produced a recombinant vesicular stomatitis virus (VSV)-based vaccine vector expressing the HBV middle envelope surface protein (MS) and found that this vector was able to efficiently generate a strong HBs-specific antibody response following a single immunization in mice. A single immunization with the VSV-MS vector also induced robust CD8 T-cell activation. The CD8 T-cell response was greater in magnitude and broader in specificity than the response generated by a vaccinia virus-based vaccine vector or by recombinant protein immunization. Furthermore, a single VSV-MS immunization provided protection against virus challenge in mice. Given the similar antibody titers and superior T-cell responses elicited from a single immunization, a VSV-based HBV vaccine may have advantages over the current recombinant protein vaccine.
b Recombinant vesicular stomatitis virus (VSV) is a promising therapeutic vaccine platform. Using a transgenic mouse model of chronic hepatitis B virus (HBV) infection, we evaluated the therapeutic potential of a VSV vector expressing the HBV middle surface envelope glycoprotein (MS). VSV-MS immunization generated HBV-specific CD8 T cell and antibody responses in trans-genic mice that express low HBV antigen levels. These findings support the further development of VSV as a therapeutic vaccine vector for chronic HBV. Despite the successful implementation of universal vaccination policies, approximately 2 billion people have been infected with hepatitis B virus (HBV), resulting in the establishment of chronic infection in more than 240 million individuals worldwide (1). Current therapeutic options for chronic HBV infection include nucleot(s)ide analogues and alpha interferon (IFN-␣), but each has a number of disadvantages. IFN-␣ treatment is effective only in a proportion of patients and is associated with significant side effects (2), while long-term treatment with nucleot(s)ide analogues rarely cures the virus and is limited by drug-resistant mutants (3). If left untreated, chronic HBV infection can result in liver cirrhosis and hepatocellular carcinoma (4). Due to the limitations of current treatment options and the risk of severe liver disease associated with chronic infection, there remains a need to develop new therapies for HBV. Host immune dysfunction, characterized by weak and ineffective T cell responses to the virus, is a key feature of chronic HBV (5). Immunomodulatory therapies such as therapeutic vaccination that are aimed at generating HBVspecific T cells with effector functions capable of eliminating the virus may provide highly efficacious treatment options for chronic HBV patients.Vesicular stomatitis virus (VSV)-based vaccine vectors generate potent HBV-specific cellular and humoral immune responses following a single dose in antigen-naïve mice (6). Additionally, in certain regimens, VSV-based vaccines generate more robust and polyfunctional CD8 T cells than DNA vaccines and other potential viral vaccine platforms (6), a finding which may be attributed to the cytopathic effects associated with VSV infection (7). The ability of VSV to generate potent CD8 T cell responses may make it better suited as a therapeutic strategy for chronic HBV infection than other immunization methods, as recovery from acute HBV infection is associated with strong, multispecific T cell responses to HBV antigens (8). Furthermore, immunization with VSV has been demonstrated to be effective as a therapeutic strategy for cervical carcinoma and other papillomavirus-associated cancers in animal models, an effect that was shown to be CD8 T cell dependent (9, 10). Therefore, we sought to determine the potential of recombinant VSV expressing the HBV middle envelope surface glycoprotein (VSV-MS) as a therapeutic vaccine for chronic HBV infection.We utilized 1.3.32 HBV transgenic (Tg) mice to examine if VSV-MS immunization can g...
bVesicular stomatitis virus (VSV) is a highly cytopathic virus being developed as a vaccine vector due to its ability to induce strong protective T cell and antibody responses after a single dose. However, little is known regarding the mechanisms underlying the potent immune responses elicited by VSV. We previously generated a VSV vector expressing the hepatitis B virus middle envelope surface glycoprotein (MS) that induces strong MS-specific T cell and antibody responses in mice. After synthesis in the cytoplasm, the MS protein translocates to the endoplasmic reticulum, where it forms subviral particles that are secreted from the cell. To better understand the contributions of secreted and intracellular protein to the VSV-induced immune response, we produced a vector expressing a secretion-deficient MS mutant (MS C69A ) and compared the immunogenicity of this vector to that of the wild-type VSV-MS vector in mice. As expected, the MS C69A protein was not secreted from VSV-infected cells and displayed enhanced proteasome-mediated degradation. Surprisingly, despite these differences in intracellular protein processing, the T cell and antibody responses generated to MS C69A were comparable to those elicited by virus expressing wild-type MS protein. Therefore, when it is expressed from VSV, the immune responses to MS are independent of particulate antigen secretion and the turnover rate of cytoplasmic protein. These results are consistent with a model in which the immune responses to VSV are strongly influenced by the replication cycle of the vector and demonstrate that characteristics of the vector have the capacity to affect vaccine efficacy more than do the properties of the antigen itself.
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