The mammalian immune system has evolved mechanisms to recognize and respond
to 'danger' signals arising from pathogens. Among those danger signals are
the unmethylated CpG dinucleotide motifs found in bacteria. At least some
of the recognition of these sequences is through cellular components of the
innate immune system, such as macrophages. Cytokines released by these cel
ls in response to CpG motifs in turn activate other immune cells, such as N
K cells and T cells, and can drive the development of adaptive immune respo
nses. These proinflammatory, Th1 responses can also be generated intentiona
lly with small oligodeoxynucleotides containing stimulatory CpG motifs, and
have beneficial properties as vaccine adjuvants and in cancer immunotherap
y. These proinflammatory responses have also been seen in gene therapy appl
ications, especially in systemic delivery systems in which plasmid DNA vect
ors have been introduced with a vehicle such as a cationic lipid. For many
gene therapy applications, finding ways to counter the immunostimulatory pr
operties of plasmid DNA vectors is an important approach designed to enhanc
e the vector safety profile, thereby increasing its effective therapeutic i
ndex. (C) 2000 Elsevier Science B.V. All rights reserved.