The role of CpG motifs in immunostimulation and gene therapy

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 cells in response to CpG motifs in turn activate other immune cells, such as NK cells and T cells, and can drive the development of adaptive immune responses. These proinflammatory, Th1 responses can also be generated intentionally with small oligodeoxynucleotides containing stimulatory CpG motifs, and have beneficial properties as vaccine adjuvants and in cancer immunotherapy. These proinflammatory responses have also been seen in gene therapy applications, especially in systemic delivery systems in which plasmid DNA vectors have been introduced with a vehicle such as a cationic lipid. For many gene therapy applications, finding ways to counter the immunostimulatory properties of plasmid DNA vectors is an important approach designed to enhance the vector safety profile, thereby increasing its effective therapeutic index.