Mouse models of acute and severe inflammation share little in common with human pathogenesis, according to a new study from a team of researchers in the US and Canada.
Acute inflammation has remained an intractable problem. While 150 clinical trials have evaluated drugs to block the inflammatory response in critically ill patients, none have been successful. "They've all failed. There is no widely accepted treatment yet," said study author Shaw Warren, a pediatrician and physician at Massachusetts General Hospital.
Drug development relies on initial results in animal models of a disease, with mice serving as the typical recruits for such studies. But growing suspicions that the mouse inflammatory response might not mirror the human condition led researchers to take a closer look at the mouse model of severe inflammation.
Funded by a National Institutes of Health (NIH) grant, the Glue Grant Consortium started by identifying patients and following them from the ambulance to the hospital and then through clinical treatment, all while mapping genome-wide expression in white blood cells and correlating the data to clinical outcomes.
The human responses were striking. Across different inflammatory conditions, white blood cells had similar gene expression patterns. That’s good news for drug developers, because it implies that a successful drug might be applicable to a range of acute inflammatory conditions.
But then the scientists analyzed the white blood cell expression profiles of mouse models of inflammation and compared them with the profiles from their human patients. When the team looked at human genes that had altered expression during inflammation, they found that mouse versions of the genes had almost no similarities. "We were all surprised at how poor the correlation was," Warren said.
The reason for that difference is unclear. Mice are distant relatives to humans, so the explanation might be found in the underlying biology of the murine immune system. It could also be an artifact of the two species' clinical experience: human burn victims receive extensive hospital treatment, whereas mice receive an injury and little else.
Regardless, the paper suggests that existing mouse models for inflammation are inadequate. In the end, researchers should consider examining a potential model more closely to see that its genetic response to inflammation is relevant to a drug's target in humans. "We're not saying don't ever use mice, but rather that perhaps the bar should be raised," says Warren.
Do the results imply problems in other mouse models? Inflammation is far from the only therapeutic area that rarely translates well from mouse models to humans. In fact, it's difficult to find one that does. "I think that should be explored. You really can't extrapolate from this work, but to the extent that many diseases have an inflammation component, it's not implausible [that the problem exists in other therapeutic areas]," says Warren.
- Seok, J., H. S. Warren, A. G. Cuenca, M. N. Mindrinos, H. V. Baker, W. Xu, D. R. Richards, G. P. McDonald-Smith, H. Gao, L. Hennessy, et al. 2013. Genomic responses in mouse models poorly mimic human inflammatory diseases. Proceedings of the National Academy of Sciences (February).