Tumour necrosis factor alpha (TNFα) is a pro-inflammatory cytokine associated with the pathogenesis of several immune-mediated diseases, such as rheumatoid arthritis and Crohn disease. Since TNFα release is a typical response to a variety of inflammatory mediators, it became an important biomarker for various diseases mediated by inflammation. Free TNFα is almost undetectable in blood of healthy organisms. However, pro-inflammatory challengers can induce TNFα expression and release of soluble TNFα after proteolytic cleavage of a precursor molecule by TNFα-converting enzyme TACE/ADAM-17.
A mechanism-based biomarker model of TNFα-response, including different external provocations of LPS challenge and test compound intervention, was developed to serve as a modelling tool.
The analysis demonstrated how to tackle a biomarker with a baseline below the limit of detection. The final model coupled to suggested guidance rules may serve as a general basis for the collection and analysis of pharmacological challenge data of future studies.
This work has been done together with Fraunhofer- Chalmers Center for Industrial Mathematics, Swedish University of Agricultural Sciences and Grünenthal GmbH Aachen Germany