Improving the therapeutic index of CpG oligodeoxynucleotides by intralymphatic administration

Signal transduction initiated by TLR such as TLR9, a natural receptor for unmethylated cytosine‐guanine‐rich motifs (CpG), results in activation of transcription factors, including NF‐κB, with substantial impact on the innate and adaptive immunity. However, practical application of new adjuvants such as CpG oligodeoxynucleotides (ODN) remains a challenge, since prominent systemic activation of NF‐κB may result in severe side effects reminiscent of septic shock, thus limiting their therapeutic index (TI). Low‐dose administration of CpG ODN into lymph nodes has been evaluated as a means to reduce systemic side effects while retaining strong adjuvant properties. To this aim, a prototype immune‐stimulating CpG ODN was used to enhance the antibody production against the antigen phospholipase A2 and the CD8+ T cell responses to ovalbumin in mice. When administered subcutaneously, high CpG ODN doses (>10 nmol) were required to enhance antibody and CD8+ T cell responses. In contrast, when administered directly into a lymph node, much lower amounts of CpG (