Anadys Uses Toll-like Receptors to Switch on Immunity

Abstract

While TLR-based programs look promising, all must contend with the fact that what works in animal studies may not map onto the human immune system closely enough for comfort. Current research may well indicate that the toll gates are not such straightforward passages to immune control. To wit: work by Jean-Laurent Casanova's research group at the Necker Medical School in Paris showed that a small group of unrelated patients who had inherited functional defects in a signaling pathway downstream of TLRs did not respond to eight of the nine receptor-specific ligands tested [2xPicard, C., Puel, A., Bonnet, M., Ku, C.L., Bustamante, J., Yang, K., Soudais, C., Dupuis, S., Feinberg, J., Fieschi, C. et al. Science. 2003; 299: 2076–2079Crossref | PubMed | Scopus (603)See all References[2]. The patients suffered from pyogenic bacteria infections with minimum inflammatory responses. Another group of patients with impaired downstream signaling from TLRs 3, 7, 8, and 9 were only susceptible to herpes simplex virus encephalitis, but otherwise healthy [3xCasrouge, A., Zhang, S.Y., Eidenschenk, C., Jouanguy, E., Puel, A., Yang, K., Alcais, A., Picard, C., Mahfoufi, N., Nicolas, N. et al. Science. 2006; 314: 308–312Crossref | PubMed | Scopus (406)See all References[3]. These findings were surprising because mice with similar defects show gross susceptibility to microbial, viral, and fungal infections. These results suggest that TLR systems in humans may be redundant and may not necessarily play as crucial a role in the innate immune system as previously thought.Drugs agonizing and antagonizing TLRs are being developed even as the rudimentary roles for the receptors in immunity are being uncovered. Toll-like receptors harbor promise for treating an amazing spectrum of maladies, possibly with fewer side effects than current drugs. But in the case of the immune system, it is wise to proceed with caution. So in short: look both ways before taking the toll road.