2019 PharmSci 360
Development of large-scale mechanistic QSP disease models often involves, as a first step, the development and calibration of mini-models, which focus on a particular subsystem of interest. Here, we illustrate this approach using interleukin-2 (IL-2) induced lymphocyte proliferation as an example. To this end we develop and calibrate an ODE-based model, which describes IL-2 binding to the IL-2 receptor, downstream phosphorylation of STAT5 and STAT5-mediated cell proliferation using in-house and published data for different lymphocyte cell types. In this way we can estimate essential parameters for our QSP platform. In addition, we find that differences in the expression levels of the alpha subunit of the IL-2 receptor as well as differences in the phosphorylation rate of STAT5 are the main factors that account for the observed differences in the sensitivity of different cell types with respect to IL-2.