| Abstrakt: |
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 A 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 (<0.1 nmol) were sufficient for a similar immune-enhancing effect. Systemic adverse reactions induced by CpG ODN were only detected at higher doses (1-10 nmol), independently of the route of administration. Finally, low-dose CpG ODN, administered in a targeted fashion to HLA-A2.1 transgenic mice, greatly elevated anti-tumor CD8 T cell immunity. Thus, intralymphatic administration of CpG ODN considerably improves the TI and may greatly enable a safe and effective use in the clinic. [ABSTRACT FROM AUTHOR] |
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