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GeneMedicine, Inc., The Woodlands, TX 77381
Administration of plasmid/lipid complexes to the lung airways may
be associated, in addition to expression of transgene, with a range of
other responses. We report here the induction of cytokines and cellular
influx in the lung airway following intratracheal administration of an
N-[1-(2–3-dioleyloxy)propyl]-N,N,N-trimethylammonium
chloride/cholesterol/plasmid positively charged complex in mice. We
show that 1) the appearance of the Th1-associated cytokines IFN-
and
IL-12 in bronchoalveolar lavage fluid is caused by unmethylated CpG
dinucleotide sequences present within the plasmid, and is enhanced by
the lipid formulation; 2) cationic lipids by themselves do not induce
IL-12 or IL-12p40; 3) TNF-
is rapidly induced by cationic lipids and
plasmid/lipid complex, but not by plasmid alone; 4) an acute cellular
influx is induced by cationic lipid alone and by a plasmid/lipid
complex, but to a much lesser extent by plasmid alone; and 5) plasmid
methylation does not influence the degree of inflammatory cell influx.
The induction of the innate immune responses by plasmid/lipid complexes
may be advantageous to gene therapy of lung diseases. In particular,
induction of the Th1 cell-promoting cytokines by plasmid/lipid
complexes could, in conjunction with an expressed transgene, be used to
modulate immune responses in the lung airways in disease conditions
that are deficient in Th1 cell responses or that have a dominant Th2
phenotype. Alternatively, the elimination of immunostimulatory
sequences in plasmids may improve the tolerability and/or efficacy of
nonviral gene therapy, especially for diseases requiring chronic
administration.
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