Abstract
Joint immunization with two recombinant adenoviruses, one expressing hepatitis C virus (HCV) core and E1 proteins and another expressing IL-12 (RAdIL-12), strongly potentiates cellular immune response against HCV Ags in BALB/c mice when RAdIL-12 was used at doses of 1 x 105-1 x 107 plaque-forming units. However, cellular immunity against HCV Ags was abolished when higher doses (1 x 108 plaque-forming units) of RAdIL-12 were used. This immunosuppressive effect was associated with marked elevation of IFN-gamma and nitric oxide in the serum and increased cell apoptosis in the spleen. Administration of N-nitro-L -arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase, to mice that received high doses of RAdIL-12 was lethal, whereas no apparent systemic toxicity by L -NAME was observed in those immunized with lower doses of the adenovirus. Interestingly, in mice immunized with recombinant adenovirus expressing core and E1 proteins of HCV in combination with RAdIL-12 at low doses (1 x 107 plaque-forming units), L -NAME inhibited T cell proliferation and CTL activity in response to HCV Ags and also production of Abs against adenoviral proteins. In conclusion, gene transfer of IL-12 can increase or abolish cell immunity against an Ag depending of the dose of the vector expressing the cytokine. IL-12 stimulates the synthesis of NO which is needed for the immunostimulating effects of IL-12, but apoptosis of T cells and immunosuppression ensues when IFN-gamma and NO are generated at very high concentrations.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenoviridae / genetics*
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Adenoviridae / immunology*
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Animals
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Antibodies, Viral / biosynthesis
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Antigens, Viral / administration & dosage
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Antigens, Viral / immunology*
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Apoptosis / immunology
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Defective Viruses / genetics
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Defective Viruses / immunology
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Dose-Response Relationship, Immunologic
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Epitopes, T-Lymphocyte / administration & dosage
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Epitopes, T-Lymphocyte / immunology
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Gene Expression Regulation / immunology
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Gene Transfer Techniques
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Genetic Vectors / administration & dosage*
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Genetic Vectors / chemical synthesis
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Genetic Vectors / immunology*
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Hepacivirus / immunology
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Immunoglobulin G / biosynthesis
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Injections, Intraperitoneal
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Interferon-gamma / blood
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Interleukin-12 / biosynthesis
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Interleukin-12 / blood
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Interleukin-12 / genetics*
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Mice
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Mice, Inbred BALB C
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NG-Nitroarginine Methyl Ester / administration & dosage
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Nitric Oxide / biosynthesis
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Nitric Oxide / physiology*
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Peritoneal Cavity / cytology
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Recombination, Genetic
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Spleen / pathology
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T-Lymphocytes / drug effects
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism
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T-Lymphocytes, Cytotoxic / immunology
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Viral Core Proteins / genetics
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Viral Core Proteins / immunology
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Viral Envelope Proteins / genetics
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Viral Envelope Proteins / immunology
Substances
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Antibodies, Viral
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Antigens, Viral
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E1 protein, Hepatitis C virus
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Epitopes, T-Lymphocyte
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Immunoglobulin G
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Viral Core Proteins
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Viral Envelope Proteins
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nucleocapsid protein, Hepatitis C virus
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Interleukin-12
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Nitric Oxide
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Interferon-gamma
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NG-Nitroarginine Methyl Ester