Improving the therapeutic index of CpG oligodeoxynucleotides by intralymphatic administration.
Eur J Immunol
; 35(6): 1869-76, 2005 Jun.
Article
em En
| MEDLINE
| ID: mdl-15909311
ABSTRACT
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-kappaB, 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-kappaB 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(2) 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.
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Base de dados:
MEDLINE
Assunto principal:
Oligodesoxirribonucleotídeos
/
Adjuvantes Imunológicos
/
Linfonodos
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2005
Tipo de documento:
Article