Regulation of innate and adaptive immunity and autoimmunity by Toll-like receptor 9

Toll-like receptors (TLRs) are a family of immune defense proteins that appear to have evolved to detect molecules that are common to broad classes of pathogens, but are not present in our own cells. Specific TLRs can be activated with synthetic ligands to induce protective or therapeutic innate and adaptive immune responses. CpG-oligodeoxynucleotides (ODN) are TLR9 ligands that have proven particularly active for immunotherapy of cancer and infectious and allergic diseases in animal models. Several CpG-ODN are now in phase I/II human clinical trials for these indications, and have shown early evidence of efficacy, with excellent safety and tolerability. Patients in cancer clinical trials have been tolerating weekly injections of CpG-ODN for longer than 6 months. Objective disease responses have been documented in five different tumor types. A few subjects have developed positive anti-dsDNA ELISAs, but antinuclear antibodies generally have been negative and the synthetic TLR9 agonists in human trials have not induced autoimmune disease. Although stimulation of the TLR9 pathway does not appear to be sufficient for induction of autoimmune disease, this pathway does appear to be required for the full development of systemic autoimmunity in some mouse models, which suggests a therapeutic role for TLR9 antagonists. These results provide new insights into the mechanism of action for the anti-rheumatic disease activity of the anti-malarials. This class of compounds had been hypothesized to act by interfering with antigen processing and presentation, but these biologic activities only occur at concentrations that are approximately two orders of magnitude above the concentrations attained in treated patients. Surprisingly, the most potent biologic activity of the anti-malarials now appears to be their inhibition of TLR9 stimulation by immunostimulatory CpG motifs. Thus, TLR9 should be considered as a validated drug target, and the classic antimalarials as relatively weak TLR9 antagonists.