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,
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Division of Basic Immunology, Department of Medicine, National Jewish Medical and Research Center, Denver, CO 80206;
Department of Dermatology, University of Colorado Health Sciences Center, Denver, CO 80262;
Department of Comparative Medicine, University of Washington, Seattle, WA 98195;
Megabios Corporation, Burlingame, CA 94010;
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Department of Pharmacology, University of Wisconsin, Madison, WI 53706; and
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Department of Immunology and the Cancer Center, University of Colorado Health Sciences Center, Denver, CO 80262
Cationic lipid-DNA complexes (CLDC) are reported to be safe and
effective for systemic gene delivery, particularly to the lungs.
However, we observed that i.v. injection of CLDC induced immunologic
effects not previously reported. We found that even very low doses of
CLDC administered i.v. induced marked systemic immune activation. This
response included strong up-regulation of CD69 expression on multiple
cell types and systemic release of high levels of Th1 cytokines, from
both lung and spleen mononuclear cells. CLDC were much more potent
immune activators on a per weight basis than either LPS or poly(I:C).
The remarkable potency of CLDC appeared to result from enhancement of
the immune stimulatory properties of DNA, since cationic lipids alone
were without immune stimulatory activity. Systemic treatment with CLDC
controlled tumor growth and significantly prolonged survival times in
mice with metastatic pulmonary tumors. NK cells accumulated to high
levels in the lungs of CLDC-treated mice, were functionally activated,
and released high levels of IFN-
. The antitumor activity induced by
CLDC injection was dependent on both NK cells and IFN-. Thus, DNA
complexed to cationic liposomes becomes highly immunostimulatory
and capable of inducing strong antitumor activity when
administered systemically.
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