The Experts below are selected from a list of 7320 Experts worldwide ranked by ideXlab platform
Hyun Seok Kang - One of the best experts on this subject based on the ideXlab platform.
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interleukin 6 il 6 and il 17 synergistically promote viral persistence by inhibiting Cellular apoptosis and cytotoxic t Cell function
Journal of Virology, 2014Co-Authors: Hyun Seok KangAbstract:Interleukin-6 (IL-6) plays an important role in the development and progression of inflammatory responses, autoimmune diseases, and cancers. Many viral infections, including Theiler's murine encephalomyelitis virus (TMEV), result in the vigorous production of IL-6. However, the role of IL-6 in the development of virus-induced inflammatory responses is unclear. The infection of susceptible mice with TMEV induces the development of chronic demyelinating disease, which is considered a relevant infectious model for multiple sclerosis. In this study, we demonstrate that resistant C57BL/6 mice carrying an IL-6 transgene (IL-6 Tg) develop a TMEV-induced demyelinating disease accompanied by an increase in viral persistence and an elevated Th17 Cell response in the central nervous system. Either IL-6 or IL-17 induced the expression of Bcl-2 and Bcl-xL at a high concentration. The upregulated expression of prosurvival molecules in turn inhibited Target Cell Destruction by virus-specific CD8+ T Cells. More interestingly, IL-6 and IL-17 synergistically promoted the expression of these prosurvival molecules, preventing Cellular apoptosis at a much lower (<5-fold) concentration. The signals involved in the synergy appear to include the activation of both STAT3 and NF-κB via distinct cytokine-dependent pathways. Thus, the excessive IL-6 promotes the generation of Th17 Cells, and the resulting IL-6 and IL-17 synergistically promote viral persistence by protecting virus-infected Cells from apoptosis and CD8+ T Cell-mediated Target Destruction. These results suggest that blocking both IL-6 and IL-17 functions are important considerations for therapies of chronic viral diseases, autoimmune diseases, and cancers. IMPORTANCE This study indicates that an excessive level of IL-6 cytokine produced following viral infection promotes the development of IL-17-producing pathogenic helper T Cells. We demonstrate here for the first time that IL-6 together with IL-17 synergistically enhances the expression of survival molecules to hinder critical host defense mechanisms removing virus-infected Cells. This finding has an important implication in controlling not only chronic viral infections but also autoimmune diseases and cancers, which are associated with prolonged Cell survival.
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th17 Cells enhance viral persistence and inhibit t Cell cytotoxicity in a model of chronic virus infection
Journal of Experimental Medicine, 2009Co-Authors: Wanqiu Hou, Hyun Seok Kang, Byung S KimAbstract:Persistent viral infection and its associated chronic diseases are a global health concern. Interleukin (IL) 17–producing Th17 Cells have been implicated in the pathogenesis of various autoimmune diseases, and in protection from bacterial or fungal infection. However, the role of Th17 Cells in persistent viral infection remains unknown. We report that Th17 Cells preferentially develop in vitro and in vivo in an IL-6–dependent manner after Theiler’s murine encephalomyelitis virus infection. Th17 Cells promote persistent viral infection and induce the pathogenesis of chronic demyelinating disease. IL-17 up-regulates antiapoptotic molecules and, consequently, increases persistent infection by enhancing the survival of virus-infected Cells and blocking Target Cell Destruction by cytotoxic T Cells. Neutralization of IL-17 augments virus clearance by eliminating virus-infected Cells and boosting lytic function by cytotoxic T Cells, leading to the prevention of disease development. Thus, these results indicate a novel pathogenic role of Th17 Cells via IL-17 in persistent viral infection and its associated chronic inflammatory diseases.
James M Wilson - One of the best experts on this subject based on the ideXlab platform.
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transduction of dendritic Cells by dna viral vectors directs the immune response to transgene products in muscle fibers
Journal of Virology, 1998Co-Authors: Karin Jooss, Yiping Yang, Krishna J Fisher, James M WilsonAbstract:Somatic gene transfer is a powerful way to elicit Cellular and humoral immune responses to a foreign protein. While this has been exploited for the development of vaccines for cancer (5, 29, 32–35, 43) and infectious disease (25, 37, 40), it is a substantial problem in the treatment of chronic diseases, such as autosomal recessive disorders, where prolonged transgene expression may be desired (4, 44). This problem has been most extensively documented following in vivo gene transfer with recombinant adenoviruses. Adenoviruses expressing the lacZ gene elicit vibrant Cellular and humoral immune responses to cytosolic β-galactosidase following delivery to liver, lung, muscle, and joint that often contribute to Destruction of the genetically corrected Target Cells and lead to inflammation and loss of transgene (14, 41, 46, 48, 52). Similar problems were encountered following low-density lipoprotein receptor gene transfer in a murine model of familial hypercholesterolemia (27). Target Cell Destruction is mediated, in part, by antigen-specific class I-restricted cytotoxic T lymphocytes (CTL) to both transgene product and newly expressed viral protein (39, 46, 47, 51, 52, 54). Activation of CD4+ T Cells, presumably of the TH1 subset, is required for the full realization of the destructive CTL effect (22, 28, 48, 50). Initial studies with recombinant adeno-associated virus (AAV) delivered to skeletal muscle have yielded unexpected results in terms of the stability of gene transfer and ensuing immune responses. This human parvovirus can be rendered defective by completely eliminating all viral open reading frames, leaving the viral capsid proteins and the product of the transgene as the only sources of antigen (26). In most cases, gene transfer with AAV has been good; however, transgene expression is often poor (9, 10, 12, 31, 36, 42). Two exceptions are skeletal muscle (11, 23, 45) and the central nervous system (21), where postmitotic, differentiated Cells such as muscle fibers and neurons are efficiently Targeted with AAV, leading to high-level and stable transgene expression. It was particularly surprising that AAV failed to elicit immune responses to highly expressed neoantigenic transgene products when injected into muscle (11, 23, 45) whereas other vector systems expressing the identical transgene, such as adenovirus (52) and naked DNA, do. We have evaluated the mechanisms by which AAV evades immunologic responses following injection into muscle in the context of rate-limiting steps of immune activation by adenovirus.
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transient subversion of cd40 ligand function diminishes immune responses to adenovirus vectors in mouse liver and lung tissues
Journal of Virology, 1996Co-Authors: Yiping Yang, Iqbal S Grewal, Richard A Flavell, R Schilz, James M WilsonAbstract:First-generation adenovirus vectors will have limited application in gene therapy for chronic diseases because of destructive host immune responses. Important immune effectors include CD8+ T Cells, which mediate Target Cell Destruction and ablate transgene expression, and B Cells, which produce neutralizing antibodies that block effective readministration of vector. Previous studies indicated that activation of CD4+ T Cells by virus capsid proteins is necessary for full realization of effector function of CD8+ T Cells and B Cells. In this paper, we present a strategy for preventing CD4+ T-Cell activation by an adenovirus vector delivered to mouse liver and lung tissues which is based on interfering with T-Cell priming via CD40 ligand-CD40 interactions. Adenovirus transgene expression was stabilized in mice genetically deficient in CD40 ligand (CD40L), and neutralizing antibody to adenovirus did not develop, allowing efficient readministration of vector. A transient blockade of T-Cell activation with an antibody to CD40L infused into the animal at the time of adenovirus vector-mediated gene transfer led to stabilization of transgene expression and diminished production of neutralizing antibody, allowing readministration of vector. In vitro T-Cell assays suggested that a block in the primary activation of CD4+ T Cells was responsible for the lack of B-Cell- and cytotoxic-T-Cell-dependent responses. This suggests a strategy for improving the potential of adenovirus vectors based on administration of an antibody to CD40L at the time of vector administration.
Byung S Kim - One of the best experts on this subject based on the ideXlab platform.
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th17 Cells enhance viral persistence and inhibit t Cell cytotoxicity in a model of chronic virus infection
Journal of Experimental Medicine, 2009Co-Authors: Wanqiu Hou, Hyun Seok Kang, Byung S KimAbstract:Persistent viral infection and its associated chronic diseases are a global health concern. Interleukin (IL) 17–producing Th17 Cells have been implicated in the pathogenesis of various autoimmune diseases, and in protection from bacterial or fungal infection. However, the role of Th17 Cells in persistent viral infection remains unknown. We report that Th17 Cells preferentially develop in vitro and in vivo in an IL-6–dependent manner after Theiler’s murine encephalomyelitis virus infection. Th17 Cells promote persistent viral infection and induce the pathogenesis of chronic demyelinating disease. IL-17 up-regulates antiapoptotic molecules and, consequently, increases persistent infection by enhancing the survival of virus-infected Cells and blocking Target Cell Destruction by cytotoxic T Cells. Neutralization of IL-17 augments virus clearance by eliminating virus-infected Cells and boosting lytic function by cytotoxic T Cells, leading to the prevention of disease development. Thus, these results indicate a novel pathogenic role of Th17 Cells via IL-17 in persistent viral infection and its associated chronic inflammatory diseases.
Yiping Yang - One of the best experts on this subject based on the ideXlab platform.
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transduction of dendritic Cells by dna viral vectors directs the immune response to transgene products in muscle fibers
Journal of Virology, 1998Co-Authors: Karin Jooss, Yiping Yang, Krishna J Fisher, James M WilsonAbstract:Somatic gene transfer is a powerful way to elicit Cellular and humoral immune responses to a foreign protein. While this has been exploited for the development of vaccines for cancer (5, 29, 32–35, 43) and infectious disease (25, 37, 40), it is a substantial problem in the treatment of chronic diseases, such as autosomal recessive disorders, where prolonged transgene expression may be desired (4, 44). This problem has been most extensively documented following in vivo gene transfer with recombinant adenoviruses. Adenoviruses expressing the lacZ gene elicit vibrant Cellular and humoral immune responses to cytosolic β-galactosidase following delivery to liver, lung, muscle, and joint that often contribute to Destruction of the genetically corrected Target Cells and lead to inflammation and loss of transgene (14, 41, 46, 48, 52). Similar problems were encountered following low-density lipoprotein receptor gene transfer in a murine model of familial hypercholesterolemia (27). Target Cell Destruction is mediated, in part, by antigen-specific class I-restricted cytotoxic T lymphocytes (CTL) to both transgene product and newly expressed viral protein (39, 46, 47, 51, 52, 54). Activation of CD4+ T Cells, presumably of the TH1 subset, is required for the full realization of the destructive CTL effect (22, 28, 48, 50). Initial studies with recombinant adeno-associated virus (AAV) delivered to skeletal muscle have yielded unexpected results in terms of the stability of gene transfer and ensuing immune responses. This human parvovirus can be rendered defective by completely eliminating all viral open reading frames, leaving the viral capsid proteins and the product of the transgene as the only sources of antigen (26). In most cases, gene transfer with AAV has been good; however, transgene expression is often poor (9, 10, 12, 31, 36, 42). Two exceptions are skeletal muscle (11, 23, 45) and the central nervous system (21), where postmitotic, differentiated Cells such as muscle fibers and neurons are efficiently Targeted with AAV, leading to high-level and stable transgene expression. It was particularly surprising that AAV failed to elicit immune responses to highly expressed neoantigenic transgene products when injected into muscle (11, 23, 45) whereas other vector systems expressing the identical transgene, such as adenovirus (52) and naked DNA, do. We have evaluated the mechanisms by which AAV evades immunologic responses following injection into muscle in the context of rate-limiting steps of immune activation by adenovirus.
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transient subversion of cd40 ligand function diminishes immune responses to adenovirus vectors in mouse liver and lung tissues
Journal of Virology, 1996Co-Authors: Yiping Yang, Iqbal S Grewal, Richard A Flavell, R Schilz, James M WilsonAbstract:First-generation adenovirus vectors will have limited application in gene therapy for chronic diseases because of destructive host immune responses. Important immune effectors include CD8+ T Cells, which mediate Target Cell Destruction and ablate transgene expression, and B Cells, which produce neutralizing antibodies that block effective readministration of vector. Previous studies indicated that activation of CD4+ T Cells by virus capsid proteins is necessary for full realization of effector function of CD8+ T Cells and B Cells. In this paper, we present a strategy for preventing CD4+ T-Cell activation by an adenovirus vector delivered to mouse liver and lung tissues which is based on interfering with T-Cell priming via CD40 ligand-CD40 interactions. Adenovirus transgene expression was stabilized in mice genetically deficient in CD40 ligand (CD40L), and neutralizing antibody to adenovirus did not develop, allowing efficient readministration of vector. A transient blockade of T-Cell activation with an antibody to CD40L infused into the animal at the time of adenovirus vector-mediated gene transfer led to stabilization of transgene expression and diminished production of neutralizing antibody, allowing readministration of vector. In vitro T-Cell assays suggested that a block in the primary activation of CD4+ T Cells was responsible for the lack of B-Cell- and cytotoxic-T-Cell-dependent responses. This suggests a strategy for improving the potential of adenovirus vectors based on administration of an antibody to CD40L at the time of vector administration.
Wanqiu Hou - One of the best experts on this subject based on the ideXlab platform.
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th17 Cells enhance viral persistence and inhibit t Cell cytotoxicity in a model of chronic virus infection
Journal of Experimental Medicine, 2009Co-Authors: Wanqiu Hou, Hyun Seok Kang, Byung S KimAbstract:Persistent viral infection and its associated chronic diseases are a global health concern. Interleukin (IL) 17–producing Th17 Cells have been implicated in the pathogenesis of various autoimmune diseases, and in protection from bacterial or fungal infection. However, the role of Th17 Cells in persistent viral infection remains unknown. We report that Th17 Cells preferentially develop in vitro and in vivo in an IL-6–dependent manner after Theiler’s murine encephalomyelitis virus infection. Th17 Cells promote persistent viral infection and induce the pathogenesis of chronic demyelinating disease. IL-17 up-regulates antiapoptotic molecules and, consequently, increases persistent infection by enhancing the survival of virus-infected Cells and blocking Target Cell Destruction by cytotoxic T Cells. Neutralization of IL-17 augments virus clearance by eliminating virus-infected Cells and boosting lytic function by cytotoxic T Cells, leading to the prevention of disease development. Thus, these results indicate a novel pathogenic role of Th17 Cells via IL-17 in persistent viral infection and its associated chronic inflammatory diseases.
