The development of a fully-integrated immune response model (FIRM) simulator of the immune response through integration of multiple subset models

BMC Systems Biology

Paolo Vicini⁴  Bernhard O Palsson³  Mary E Spilker⁴  Peter J O’Brien⁴  Karin Jooss¹  Michael Zager⁴  Erica L Bradshaw-Pierce²  Timothy P Hickling⁵  Sirus Palsson³ 

[1] Vaccines Research Unit, Pfizer Worldwide Research and Development, San Diego, CA, USA;Current address: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy, University of Colorado Anschutz Medical Campus, Aurora, CO, USA;GT Life Sciences, San Diego, CA, USA;Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research and Development, San Diego, CA, USA;Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research and Development, Sandwich, UK

关键词: Systems biology;    Ordinary differential equation systems;    Mathematical modeling;    Immune response;    Biological networks;   

Others  :  1142194
DOI  :  10.1186/1752-0509-7-95

 received in 2012-11-15, accepted in 2013-08-21,  发布年份 2013

【 摘 要 】

Background

The complexity and multiscale nature of the mammalian immune response provides an excellent test bed for the potential of mathematical modeling and simulation to facilitate mechanistic understanding. Historically, mathematical models of the immune response focused on subsets of the immune system and/or specific aspects of the response. Mathematical models have been developed for the humoral side of the immune response, or for the cellular side, or for cytokine kinetics, but rarely have they been proposed to encompass the overall system complexity. We propose here a framework for integration of subset models, based on a system biology approach.

Results

A dynamic simulator, the Fully-integrated Immune Response Model (FIRM), was built in a stepwise fashion by integrating published subset models and adding novel features. The approach used to build the model includes the formulation of the network of interacting species and the subsequent introduction of rate laws to describe each biological process. The resulting model represents a multi-organ structure, comprised of the target organ where the immune response takes place, circulating blood, lymphoid T, and lymphoid B tissue. The cell types accounted for include macrophages, a few T-cell lineages (cytotoxic, regulatory, helper 1, and helper 2), and B-cell activation to plasma cells. Four different cytokines were accounted for: IFN-γ, IL-4, IL-10 and IL-12. In addition, generic inflammatory signals are used to represent the kinetics of IL-1, IL-2, and TGF-β. Cell recruitment, differentiation, replication, apoptosis and migration are described as appropriate for the different cell types. The model is a hybrid structure containing information from several mammalian species. The structure of the network was built to be physiologically and biochemically consistent. Rate laws for all the cellular fate processes, growth factor production rates and half-lives, together with antibody production rates and half-lives, are provided. The results demonstrate how this framework can be used to integrate mathematical models of the immune response from several published sources and describe qualitative predictions of global immune system response arising from the integrated, hybrid model. In addition, we show how the model can be expanded to include novel biological findings. Case studies were carried out to simulate TB infection, tumor rejection, response to a blood borne pathogen and the consequences of accounting for regulatory T-cells.

Conclusions

The final result of this work is a postulated and increasingly comprehensive representation of the mammalian immune system, based on physiological knowledge and susceptible to further experimental testing and validation. We believe that the integrated nature of FIRM has the potential to simulate a range of responses under a variety of conditions, from modeling of immune responses after tuberculosis (TB) infection to tumor formation in tissues. FIRM also has the flexibility to be expanded to include both complex and novel immunological response features as our knowledge of the immune system advances.

【 授权许可】

   
2013 Palsson et al.; licensee BioMed Central Ltd.

【 图 表 】

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