Reply to Cauwels et al.: Of men, not mice, and inflammation

Abstract

We appreciate the comments of Cauwels et al. (1) regarding our recent publication (2). Cauwels et al. cite the use of anti-TNF treatment for rheumatoid arthritis and inflammatory bowel disease and the failure of nitric oxide (NO) synthases in sepsis as examples of the successful use of mouse models. Ironically, these examples could in fact be used to illustrate the differences between mice and humans. Anti-TNF treatment was developed for the treatment of sepsis because it protected mice in models of sepsis (3). However, anti-TNF failed in human trials of sepsis (4). It was only later that anti-TNF was shown to be helpful for rheumatoid arthritis and inflammatory bowel disease. In the case of NO, it should be noted that although mouse macrophages readily produce NO in vitro, human macrophages do not (5). The many trials for sepsis in which drugs protected in mice but failed in humans suggest that ability of mouse efficacy models to predict human inflammatory diseases is close to random, and therefore it should not be surprising that occasionally there is a correlation. However, for such a model to be helpful, it needs to prospectively predict the human condition. In this case, mouse models appear to perform very poorly indeed.