Towards a systems biology model for inflammatory bowel disease
Sabine Stübler (1,2), Charlotte Kloft (3), Wilhelm Huisinga (4)
(1) PharMetrX Graduate Research Training Program: Pharmacometrics & Computational Disease Modelling, Freie Universität Berlin/Universität Potsdam, (2) Institut für Biochemie und Biologie, Universität Potsdam, (3) Institut für Pharmazie, Freie Universität Berlin, (4) Institut für Mathematik, Universität Potsdam
Objectives: Inflammatory bowel disease (IBD) (major forms: Crohn’s disease and Ulcerative colitis) is a chronic disease caused by autoimmunity of T cells against commensal bacteria in the gut. Different treatments, such as immunomodulatory small molecule drugs or monoclonal antibodies (mAbs) targeting TNF-a, are in use, but the therapeutic outcome differs highly between patients. The objective was to mathematically describe the cellular processes of the intestinal immune system to provide a basis for further analysis of drug effects and inter-individual variability.
Methods: Based on the main aspects of a previously published systems biology model of IBD [1] and extensive literature research, we developed an ODE model comprising the dynamics and interactions of different immune cell types (naive, memory, helper and regulatory T cells and dendritic cells in different activation states) in the mesenteric lymph nodes and intestinal lamina propria.
Results: The developed ODE model described activation and antigen uptake by dendritic cells, dendritic cell interaction with naive and memory T cells leading to T cell proliferation and differentiation into effector T cells (helper T cells and induced regulatory T cells, depending on the dendritic cells’ activation status), and effector T cell activation by further contact to antigen-presenting dendritic cells. Inhibition of dendritic cell and T cell activation by induced and natural regulatory T cells formed a negative feedback loop. To calculate the cytokine-dependent apoptosis rate of helper and regulatory T cells, induced by re-stimulation with antigen or cytokine deprivation, interleukin-2 was included into the model. Experimentally known healthy steady state levels from the literature (dendritic cells in LP, natural regulatory T cells in MLN and LP, induced regulatory T cells in MLN and LP and memory T cells in MLN and LP) are well described by the model. Further requirements to describe the pathological mechanisms of IBD and to simulate treatment include integration of macrophages and neutrophils, representing the innate immune system, and bacteria, which elicit the immune response.
Conclusions: This is a first step towards a systems biology model to describe the cellular dynamics in IBD.
References:
[1] Wendelsdorf, K., Bassaganya-Riera, J., Hontecillas, R., & Eubank, S. (2010). Model of colonic inflammation: immune modulatory mechanisms in inflammatory bowel disease. Journal of theoretical biology, 264(4), 1225-1239.
