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), with its major forms Crohn’s disease and Ulcerative colitis, is a chronic disease caused by autoimmunity of T cells against commensal bacteria in the gut. Current treatment regimens include corticosteroids, immunomodulatory small molecule drugs and monoclonal antibodies (mAbs) targeting TNF-a, but the therapeutic outcome differs highly between patients. A better understanding of the mucosal immune system in the context of inflammatory bowel disease is therefore highly desirable. The objective of this work 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: We identified important processes of the mucosal immune system (innate and adaptive) on the cellular level through an extensive literature research. These processes were described (i) in terms of literature values as parameters, (ii) by fitting parameters to literature data from human, mouse or in vitro studies, or (iii) by assuming reasonable parameter ranges resulting in adequate model behaviour, where literature data were not available. We combined these processes into a systems biology model that described concentrations of several cell types in the gut lamina propria and the mesenteric lymph nodes.
Results: The developed ODE model included dendritic cells, (naive, memory, helper and regulatory) T cells, macrophages, neutrophils and bacterial cells. Dendritic cells in the lamina propria were present in four different states depending on their inflammatory status and uptake of antigen. Macrophages in the lamina propria were modelled by transitional compartments, from a pro-inflammatory to anti-inflammatory status (as shown in [1]). Neutrophils were recruited when bacteria penetrated into the lamina propria and died from apoptosis, where apoptotic neutrophils increased neutrophil apoptosis and inhibited neutrophil recruitment, resulting in self-limiting neutrophil invasion. Bacterial killing by neutrophils, dendritic cells and macrophages was modelled by using a maximal killing rate per phagocyte, resulting in a critical phagocyte concentration needed for bacterial elimination (as proposed by [2]). In the mesenteric lymph nodes dendritic cells presenting bacterial antigen activated naive and memory T cells expressing the specific T cell receptor, which differentiated into helper T cells that further stimulated the innate immune system or regulatory T cells that limited the extent of the inflammation. As their half-lives are comparably small on the time-scale of the modelled cells, pro-inflammatory and anti-inflammatory cytokines were included implicitly in the model, as linear combinations of the producing cells. Pro- and anti-inflammatory cytokines were assigned opposing effects in the activation of dendritic cells and in the de-activating transition between macrophage subsets. In addition, pro-inflammatory cytokines increased leukocyte recruitment into lamina propria.
The model was able to reflect the main characteristics of the mucosal immune system: Bacteria up to a threshold concentration were efficiently cleared in the model. As first line of defence neutrophils infiltrated the lamina propria, dendritic cells and macrophages followed. Dendritic cells and macrophages shifted to an inflammatory state upon activation and recovered when the bacteria were eliminated. Effector T cell concentrations increased with a delay. After the acute inflammation all cell concentrations returned to baseline.
Regarding the aim of describing the cellular dynamics in IBD, we identified several steps that are further required. Different IBD triggers known from literature will be translated into model inputs and tested for the result of chronic inflammation in the model. A virtual population of patients will then be generated by different trigger combinations leading to chronic inflammation. To simulate treatment, drug PK and actions will be included (e.g. anti-TNF-alpha mAbs and interaction with TNF-alpha).
Conclusions: The developed systems biology model was able to reflect the main characteristics of the mucosal immune system. This is a promising first step towards modelling the pathological processes and drug effects in IBD.
References:
[1] Bain, C. C., Scott, C. L., Uronen-Hansson, H., Gudjonsson, S., Jansson, O., Grip, O., … & Mowat, A. M. (2013). Resident and pro-inflammatory macrophages in the colon represent alternative context-dependent fates of the same Ly6C hi monocyte precursors. Mucosal immunology, 6(3), 498.
[2] Li, Y., Karlin, A., Loike, J. D., & Silverstein, S. C. (2004). Determination of the critical concentration of neutrophils required to block bacterial growth in tissues. Journal of Experimental Medicine, 200(5), 613-622.
Reference: PAGE 27 (2018) Abstr 8742 [www.page-meeting.org/?abstract=8742]
Poster: Drug/Disease Modelling - Other Topics