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The science behind mechanistic immune intelligence

Peer-reviewed research by ImmuNovus founder Tomáš Helikar and colleagues at the University of Nebraska–Lincoln and collaborating institutions demonstrates how mechanistic models can connect immune responses, identify therapeutic targets, and explain behavior across biological scales.

Featured research

  • Modeling the connected immune system

    A mechanistic model spanning 11 disease contexts connects immune cells and secreted signals to simulate responses to infection, autoimmunity, and lung transplantation. The study evaluated its predictions in 38 validation experiments against published observations.

    11
    disease contexts
    1,450
    regulatory interactions
    38
    validation experiments

    Moore et al. · Frontiers in Immunology · 2026

    A comprehensive mechanistic multicellular model of the human immune system spanning 11 diseases

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  • Identifying therapeutic targets

    Disease-specific metabolic models identified 68 candidate drug targets across three autoimmune diseases. In vitro experiments combined with published evidence supported CD4+ T-cell suppression for half of the identified targets.

    68
    candidate targets
    3
    autoimmune diseases

    Puniya et al. · npj Systems Biology and Applications · 2021

    Integrative computational approach identifies drug targets in CD4+ T-cell-mediated immune disorders

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  • Connecting molecular mechanisms to immune behavior

    A CD4+ T-cell model integrated signaling, metabolism, cell populations, and cytokine dynamics using four modeling approaches. It reproduced published experimental behaviors and predicted emergent immune responses arising across scales.

    4
    modeling approaches
    3
    spatial scales

    Wertheim et al. · PLOS Computational Biology · 2021

    A multi-approach and multi-scale platform to model CD4+ T cells responding to infections

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Published CD4+ T-cell research has demonstrated multiscale integration. ImmuNovus is extending this approach across additional immune cell types and disease contexts.

Supporting studies

  • Connecting immune-cell signaling and communication

    A mechanistic dendritic-cell model links intracellular signaling with cell–cell communication and explores immune responses in infection and cancer contexts.

    Aghamiri et al. · Frontiers in Immunology · 2023

    A multiscale mechanistic model of human dendritic cells for in-silico investigation of immune responses and novel therapeutics discovery

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  • Integrating multi-omics into metabolic models

    COMO provides a pipeline for integrating multi-omics data into metabolic modeling for drug-discovery research.

    Briefings in Bioinformatics · 2023

    COMO: a pipeline for multi-omics data integration in metabolic modeling and drug discovery

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Shaping the future of immune digital twins

Alongside original research, Helikar and collaborators have contributed roadmaps and perspectives on the development and application of mechanistic immune digital twins.

  • Building digital twins of the human immune system: toward a roadmap

    npj Digital Medicine · 2022

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  • Toward mechanistic medical digital twins: some use cases in immunology

    Frontiers in Digital Health · 2024

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Explore all publications

56 publications

Immune digital twins

  • Building digital twins of the human immune system: toward a roadmap

    npj Digital Medicine · 2022

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  • Toward mechanistic medical digital twins: some use cases in immunology

    Frontiers in Digital Health · 2024

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  • Forum on immune digital twins: a meeting report

    npj Systems Biology and Applications · 2024

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  • Modeling and remodeling the cell: how digital twins and HCMV can elucidate the complex interactions of viral latency, epigenetic regulation, and immune responses

    Current Clinical Microbiology Reports · 2023

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Immune cell modeling

  • A comprehensive mechanistic multicellular model of the human immune system spanning 11 diseases

    Frontiers in Immunology · 2026

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  • A multi-approach and multi-scale platform to model CD4+ T cells responding to infections

    PLOS Computational Biology · 2021

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  • A multiscale mechanistic model of human dendritic cells for in-silico investigation of immune responses and novel therapeutics discovery

    Frontiers in Immunology · 2023

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  • A mechanistic computational model reveals that plasticity of CD4+ T cell differentiation is a function of cytokine composition and dosage

    Frontiers in Physiology · 2018

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  • Simulation of stimulation: cytokine dosage and cell cycle crosstalk driving timing-dependent T cell differentiation

    Frontiers in Physiology · 2018

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  • Design, assessment, and in vivo evaluation of a computational model illustrating the role of CAV1 in CD4+ T-lymphocytes

    Frontiers in Immunology · 2014

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  • Combined TLR4 and TLR9 agonists induce distinct phenotypic changes in innate immunity in vitro and in vivo

    Cellular Immunology · 2020

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Drug discovery, repurposing, and target identification

  • Integrative computational approach identifies drug targets in CD4+ T-cell-mediated immune disorders

    npj Systems Biology and Applications · 2021

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  • COMO: a pipeline for multi-omics data integration in metabolic modeling and drug discovery

    Briefings in Bioinformatics · 2023

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  • Systems perturbation analysis of a large-scale signal transduction model reveals potentially influential candidates for cancer therapeutics

    Frontiers in Bioengineering and Biotechnology · 2016

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  • Drug-target identification in COVID-19 disease mechanisms using computational systems biology approaches

    Frontiers in Immunology · 2024

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  • Integrative network analyses of transcriptomics data reveal potential drug targets for acute radiation syndrome

    Scientific Reports · 2021

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  • Identification of potential prophylactic medical countermeasures against acute radiation syndrome (ARS)

    International Journal of Molecular Sciences · 2025

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  • A review of radiation-induced alterations of multi-omic profiles, radiation injury biomarkers, and countermeasures

    Radiation Research · 2022

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Host–pathogen interactions

  • Dynamics of influenza virus and human host interactions during infection and replication cycle

    Bulletin of Mathematical Biology · 2012

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  • Molecular phylogeny and evolutionary dynamics of influenza A nonstructural (NS) gene

    Infection, Genetics and Evolution · 2014

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  • COVID-19 Disease Map, a computational knowledge repository of virus–host interaction mechanisms

    Molecular Systems Biology · 2021

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  • Arginine catabolism and polyamine biosynthesis pathway disparities within Francisella tularensis subpopulations

    Frontiers in Microbiology · 2022

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  • Differences in blood-derived Francisella tularensis type B strains from clinical cases of tularemia

    Microorganisms · 2020

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Mechanistic network modeling

  • Emergent decision-making in biological signal transduction networks

    PNAS · 2008

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  • A comprehensive, multi-scale dynamical model of ErbB receptor signal transduction in human mammary epithelial cells

    PLoS ONE · 2013

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  • The Cell Collective: toward an open and collaborative approach to systems biology

    BMC Systems Biology · 2012

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  • Bio-Logic Builder: a non-technical tool for building dynamical, qualitative models

    PLoS ONE · 2012

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  • ChemChains: a platform for simulation and analysis of biochemical networks aimed to laboratory scientists

    BMC Systems Biology · 2009

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  • Ergodic sets as cell phenotype of budding yeast cell cycle

    PLoS ONE · 2012

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  • Sensitivity analysis of biological Boolean networks using information fusion based on nonadditive set functions

    BMC Systems Biology · 2014

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  • Identification of biologically essential nodes via determinative power in logical models of cellular processes

    Frontiers in Physiology · 2018

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  • Automated inference of Boolean models from molecular interaction maps using CaSQ

    Bioinformatics · 2020

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  • Augusta: from RNA-Seq to gene regulatory networks and Boolean models

    Computational and Structural Biotechnology Journal · 2024

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  • A practical guide to mechanistic systems modeling in biology using a logic-based approach

    Briefings in Bioinformatics · 2020

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  • Logical modeling and dynamical analysis of cellular networks

    Frontiers in Genetics · 2016

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  • ccNetViz: a WebGL-based JavaScript library for visualization of large networks

    Bioinformatics · 2020

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  • Programmatic access to logical models in the Cell Collective modeling environment via a REST API

    Biosystems · 2016

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Quantitative systems pharmacology and AI

  • Recent applications of quantitative systems pharmacology and machine learning models across diseases

    Journal of Pharmacokinetics and Pharmacodynamics · 2021

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  • Two heads are better than one: current landscape of integrating QSP and machine learning

    Journal of Pharmacokinetics and Pharmacodynamics · 2022

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  • AI-driven applications in clinical pharmacology and translational science: insights from the ASCPT 2024 AI preconference

    Clinical and Translational Science · 2025

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Cancer biomarkers

  • CancerDiscover: an integrative pipeline for cancer biomarker and cancer class prediction from high-throughput sequencing data

    Oncotarget · 2017

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  • Identification of potential tissue-specific cancer biomarkers and development of cancer versus normal genomic classifiers

    Oncotarget · 2017

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Metabolism and disease

  • Essential role of systemic iron mobilization and redistribution for adaptive thermogenesis through the HIF2-α/hepcidin axis

    PNAS · 2021

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  • Aberrant energy metabolism and redox balance in seizure onset zones of epileptic patients

    Journal of Proteomics · 2020

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  • Changes in lipid profiles of epileptic mouse model

    Metabolomics · 2020

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  • Computational systems biology approach for the study of rheumatoid arthritis: from a molecular map to a dynamical model

    Genomics and Computational Biology · 2017

Modeling standards and community infrastructure

  • SBML Level 3: an extensible format for the exchange and reuse of biological models

    Molecular Systems Biology · 2020

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  • SBML qualitative models: a model representation format and infrastructure to foster interactions between qualitative modelling formalisms and tools

    BMC Systems Biology · 2013

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  • The simulation experiment description markup language (SED-ML): level 1 version 4

    Journal of Integrative Bioinformatics · 2021

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  • The simulation experiment description markup language (SED-ML): level 1 version 5

    Journal of Integrative Bioinformatics · 2024

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  • The CoLoMoTo interactive notebook: accessible and reproducible computational analyses for qualitative biological networks

    Frontiers in Physiology · 2018

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  • Cooperative development of logical modelling standards and tools with CoLoMoTo

    Bioinformatics · 2015

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  • SysMod: the ISCB community for data-driven computational modelling and multi-scale analysis of biological systems

    Bioinformatics · 2021

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  • Setting the basis of best practices and standards for curation and annotation of logical models in biology

    Briefings in Bioinformatics · 2020

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  • Addressing barriers in comprehensiveness, accessibility, reusability, interoperability and reproducibility of computational models in systems biology

    Briefings in Bioinformatics · 2022

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  • Computational modelling in health and disease: highlights of the 6th annual SysMod meeting

    Bioinformatics · 2022

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