Heterogeneity in the human response to immunostimulatory CpG oligodeoxynucleotides

Synthetic oligodeoxynucleotides (ODNs) containing unmethylated CpG motifs trigger an immune response characterized by proliferation, B-cell activation, and cytokine production. CpG ODNs show promise in animal models as vaccine adjuvants and anti-allergens and for the treatment of infectious diseases and cancer. Several different CpG motifs capable of stimulating human cells have been identified, and several CpG-containing ODNs are now in various stages of clinical trials. However, little is known of the comparative magnitude or breadth of the immune responses these CpG ODNs elicit. This work compares the proliferative, IgM, and IL-6 response of PBMCs from 100 normal donors to a panel of 11 ODNs selected as highly active from over 100 phosphorothioate ODNs. While PBMCs from every donor responded to at least one member of the ODN panel, no single ODN was optimally stimulatory in all subjects or for all responses. A mixture of ODNs with complementary activities induced significantly broader stimulation of donor PBMCs than any single ODN, providing a rational basis for proceeding into clinical trials with such a mixture.