In a previous post we reported on a study that shows that mice may not be a good model for human diabetes. A new study now provides a mechanistic explanation for the well-documented toxicity invoked by Toll-like receptor 9 (TLR9) signalling in rodents, which is not observed in humans or non-human primates. Immunostimulatory DNA sequences (ISS) containing CpG (cytosine-phosphate-guanine) motifs which signal through TLR9 are being developed to treat asthma. These are safe and well tolerated in both healthy human volunteers and asthmatics when delivered to the airways, but cause lung inflammation and weight loss in mice at therapeutic doses. Writing in the Journal of Clinical Investigation, scientists at Dynavax Technologies Corporation and Astra Zeneca have shown that these differences in toxicity can be explained by differential TLR9 expression patterns in humans and rodents. In humans, TLR9 expression in mononuclear blood cells and lymphoid organs is restricted to B cells and plasmacytoid dendritic cells whereas, in mice, TLR9 is additionally expressed on macrophages, myeloid dendritic cells and activated T-cells. An investigation into the cell types and cytokines responsible for ISS-induced toxicity in mice showed that this could largely be attributed to production of TNF-α by monocytes and macrophages, cells that do not express TLR9 in primates.
The authors conclude that this fundamental difference in TLR9 expression patterns accounts for much of the exaggerated toxicity observed in rodents exposed to high doses of ISS in the respiratory tract. The new mechanistic insights into species-specific toxicities should help in the interpretation of toxicology studies of ISS in animals.