Determining disease intervention strategies using spatially resolved simulations

Mark Read, Paul S. Andrews, Jon Timmis, Richard A. Williams, Richard B. Greaves, Huiming Sheng, Mark Coles, Vipin Kumar

Research output: Contribution to journalArticlepeer-review

14 Citations (SciVal)

Abstract

Predicting efficacy and optimal drug delivery strategies for small molecule and biological therapeutics is challenging due to the complex interactions between diverse cell types in different tissues that determine disease outcome. Here we present a new methodology to simulate inflammatory disease manifestation and test potential intervention strategies in silico using agent-based computational models. Simulations created using this methodology have explicit spatial and temporal representations, and capture the heterogeneous and stochastic cellular behaviours that lead to emergence of pathology or disease resolution. To demonstrate this methodology we have simulated the prototypic murine T cell-mediated autoimmune disease experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. In the simulation immune cell dynamics, neuronal damage and tissue specific pathology emerge, closely resembling behaviour found in the murine model. Using the calibrated simulation we have analysed how changes in the timing and efficacy of T cell receptor signalling inhibition leads to either disease exacerbation or resolution. The technology described is a powerful new method to understand cellular behaviours in complex inflammatory disease, permits rational design of drug interventional strategies and has provided new insights into the role of TCR signalling in autoimmune disease progression.

Original languageEnglish
Article numbere80506
JournalPLoS One
Volume8
Issue number11
DOIs
Publication statusPublished - 14 Nov 2013

Keywords

  • Animals
  • Autoimmune Diseases/immunology
  • Computer Simulation
  • Disease Models, Animal
  • Encephalomyelitis, Autoimmune, Experimental/immunology
  • Female
  • Mice
  • Mice, Inbred C57BL
  • T-Lymphocytes, Regulatory/metabolism

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