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*
Laboratory of Experimental Immunology, Division of Basic Sciences;
Department of Experimental Transplantation and Immunology, Division of Clinical Sciences; and
Intramural Research Support Program, Science Applications International Corp., National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, MD 21702;
§
Pediatric Oncology Branch, Division of Clinical Sciences, National Cancer Institute, Bethesda, MD 20892; and
¶
EntreMed, Inc., Rockville, MD 20850
In this study four murine IL-12 naked DNA expression plasmids
(pIL-12), containing both the p35 and p40 subunits, were shown to
induce systemic biological effects in vivo after intradermal injection.
Three of the four IL-12 expression vectors augmented NK activity and
induced expression of the IFN-
and IFN--inducible Mig genes. Both
IL-12 p70 heterodimer and IFN- proteins were documented in the serum
within 24 h after intradermal injection of the
pIL-12o- plasmid, which also induced the highest level of
NK activity in the spleen and liver among the IL-12 constructs.
Interestingly, both p40 mRNA expression at the injection site and serum
protein levels followed a biphasic pattern of expression, with peaks on
days 1 and 5. Subsequent studies revealed that the ability of
intradermally injected pIL-12o- to augment NK lytic
activity was prevented by administration of a neutralizing
anti-IL-12 mAb. Finally, injection of the pIL-12o-
into BALB/c IL-12 p40-/- mice also resulted in a biphasic
pattern of IL-12 p70 appearance in the serum, and induced IFN-
protein and activated NK lytic activity in liver and
spleen. These results demonstrate that injection of delivered naked DNA
encoding the IL-12 gene mediates the biphasic systemic production of
IL-12-inducible genes and augments the cytotoxic function of NK cells
in lymphoid and parenchymal organs as a direct result of transgene
expression. The results also suggest that these naked DNA plasmids may
be useful adjuvants for vaccines against infectious and neoplastic
diseases.
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