Different doses of adenoviral vector expressing IL-12 enhance or depress the immune response to a coadministered antigen: the role of nitric oxide.
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.
Lasarte
J J
JJ
Department of Internal Medicine, Medical School and University Clinic, University of Navarra, Pamplona, Spain.
Corrales
F J
FJ
Casares
N
N
López-Díaz de Cerio
A
A
Qian
C
C
Xie
X
X
Borrás-Cuesta
F
F
Prieto
J
J
D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology*; D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis; D000956:Antigens, Viral / Q000008:administration & dosage / Q000276:immunology*; D017209:Apoptosis / Q000276:immunology; D003673:Defective Viruses / Q000235:genetics / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000008:administration & dosage / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000276:immunology*; D016174:Hepacivirus / Q000276:immunology; D007074:Immunoglobulin G / Q000096:biosynthesis; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000097:blood; D018664:Interleukin-12 / Q000096:biosynthesis / Q000097:blood / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage; D009569:Nitric Oxide / Q000096:biosynthesis / Q000502:physiology*; D010529:Peritoneal Cavity / Q000166:cytology; D011995:Recombination, Genetic; D013154:Spleen / Q000473:pathology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014758:Viral Core Proteins / Q000235:genetics / Q000276:immunology; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology
D000914:Antibodies, Viral; D000956:Antigens, Viral; C087035:E1 protein, Hepatitis C virus; D018984:Epitopes, T-Lymphocyte; D007074:Immunoglobulin G; D014758:Viral Core Proteins; D014759:Viral Envelope Proteins; C069130:nucleocapsid protein, Hepatitis C virus; D018664:Interleukin-12; D009569:Nitric Oxide; D007371:Interferon-gamma; D019331:NG-Nitroarginine Methyl Ester