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Different Doses of Adenoviral Vector Expressing IL-12 Enhance or Depress the Immune Response to a Coadministered Antigen: the Role of Nitric Oxide¹

Department of Internal Medicine, Medical School and University Clinic, University of Navarra, Pamplona, Spain

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- 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- and NO are generated at very high concentrations.

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