Induction of long-lasting cytokine effect by injection of IL-12 encoding plasmid DNA

• Published in: Cancer gene therapy Vol. 7; no. 12; pp. 1557 - 1565
• Main Authors: Schultz, J, Heinzerling, L, Pavlovic, J, Moelling, K
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.12.2000
• Subjects: Animals; Antigen-Presenting Cells - immunology; Autocrine signalling; CD8-Positive T-Lymphocytes - immunology; CpG islands; CpG Islands - genetics; Deoxyribonucleic acid; DNA; DNA - genetics; DNA Primers - chemistry; Enzyme-Linked Immunosorbent Assay; Gene therapy; Gene Transfer Techniques; Immune system; Injection; Injections, Intramuscular; Interferon-gamma - biosynthesis; Interleukin 12; Interleukin 4; Interleukin-12 - biosynthesis; Interleukin-12 - genetics; Killer Cells, Natural - immunology; Lung Neoplasms - therapy; Lymphocyte Depletion; Melanoma; Melanoma, Experimental - metabolism; Melanoma, Experimental - therapy; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Natural killer cells; Oligonucleotides; Tumor necrosis factor-α; Tumors; Vaccines, DNA - therapeutic use; γ-Interferon
• ISSN: 0929-1903; 1476-5500
• DOI: 10.1038/sj.cgt.7700273

We have recently demonstrated that DNA coding for both subunits of the murine IL-12 heterodimer exhibits a strong antimetastatic effect against B16-melanoma in C57BL/6 mice and after intratumoral injection tumor regression. Here we show that the antimetastatic effect can be detected when the DNA is injected intramuscularly 30 days before tumor cell challenge. A long-term IL-12 expression was measured for up to 50 days in the serum with a peak at day 20 amounting to about 10 ng/mL in C57BL/6 mice. CpG oligodeoxynucleotides also induce IL-12 expression, however, only for a few hours. IL-12 DNA administration induces long-lasting systemic IFN -gamma production, whereas IL-4 and TNF-alpha levels remained undetectable. NK cell-depleted mice showed a strong but reduced expression of murine IL-12. Expression of DNA encoding human instead of murine IL-12 resulted in a significantly lower and transient expression, indicating that not plasmid-derived IL-12 production alone but the immune system of the host contributes to the long- lasting antimetastatic effect. It may be attributable to an autocrine feedback mechanism maintaining murine IL- 12 expression, whereby several cell populations including NK cells are involved.