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Article: Establishment of maternal blood supply to the placenta: insights into plugging, unplugging and trophoblast behaviour from an agent-based model.

Saghian, Rojan / Bogle, Gib / James, Joanna L / Clark, Alys R

Interface focus

2019 Volume 9, Issue 5, Page(s) 20190019

Abstract: The ability of the baby to receive nutrients and ... ...

Abstract	The ability of the baby to receive nutrients and oxygen
Language	English
Publishing date	2019-08-16
Publishing country	England
Document type	Journal Article
ISSN	2042-8898
ISSN	2042-8898
DOI	10.1098/rsfs.2019.0019
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Article ; Online: Three-dimensional Imaging Reveals Immune-driven Tumor-associated High Endothelial Venules as a Key Correlate of Tumor Rejection Following Depletion of Regulatory T Cells.

Milutinovic, Stefan / Abe, Jun / Jones, Emma / Kelch, Inken / Smart, Kathryn / Lauder, Sarah N / Somerville, Michelle / Ware, Carl / Godkin, Andrew / Stein, Jens V / Bogle, Gib / Gallimore, Awen

Cancer research communications

2023 Volume 2, Issue 12, Page(s) 1641–1656

Abstract: High endothelial venules (HEV) are specialized post capillary venules that recruit naïve T cells and B cells into secondary lymphoid organs (SLO) such as lymph nodes (LN). Expansion of HEV networks in SLOs occurs following immune activation to support ... ...

Abstract	High endothelial venules (HEV) are specialized post capillary venules that recruit naïve T cells and B cells into secondary lymphoid organs (SLO) such as lymph nodes (LN). Expansion of HEV networks in SLOs occurs following immune activation to support development of an effective immune response. In this study, we used a carcinogen-induced model of fibrosarcoma to examine HEV remodeling after depletion of regulatory T cells (Treg). We used light sheet fluorescence microscopy imaging to visualize entire HEV networks, subsequently applying computational tools to enable topological mapping and extraction of numerical descriptors of the networks. While these analyses revealed profound cancer- and immune-driven alterations to HEV networks within LNs, these changes did not identify successful responses to treatment. The presence of HEV networks within tumors did however clearly distinguish responders from nonresponders. Finally, we show that a successful treatment response is dependent on coupling tumor-associated HEV (TA-HEV) development to T-cell activation implying that T-cell activation acts as the trigger for development of TA-HEVs which subsequently serve to amplify the immune response by facilitating extravasation of T cells into the tumor mass.
MeSH term(s)	Humans ; T-Lymphocytes, Regulatory ; Venules ; Imaging, Three-Dimensional ; Neoplasms ; Lymph Nodes
Language	English
Publishing date	2023-01-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2767-9764
ISSN (online)	2767-9764
DOI	10.1158/2767-9764.CRC-21-0123
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Article ; Online: A virtual lymph node model to dissect the requirements for T-cell activation by synapses and kinapses.

Moreau, Hélène D / Bogle, Gib / Bousso, Philippe

Immunology and cell biology

2016 Volume 94, Issue 7, Page(s) 680–688

Abstract: The initiation of T-cell responses in lymph nodes requires T cells to integrate signals delivered by dendritic cells (DCs) during long-lasting contacts (synapses) or more transient interactions (kinapses). However, it remains extremely challenging to ... ...

Abstract	The initiation of T-cell responses in lymph nodes requires T cells to integrate signals delivered by dendritic cells (DCs) during long-lasting contacts (synapses) or more transient interactions (kinapses). However, it remains extremely challenging to understand how a specific sequence of contacts established by T cells ultimately dictates T-cell fate. Here, we have coupled a computational model of T-cell migration and interactions with DCs with a real-time, flow cytometry-like representation of T-cell activation. In this model, low-affinity peptides trigger T-cell proliferation through kinapses but we show that this process is only effective under conditions of high DC densities and prolonged antigen availability. By contrast, high-affinity peptides favor synapse formation and a vigorous proliferation under a wide range of antigen presentation conditions. In line with the predictions, decreasing the DC density in vivo selectively abolished proliferation induced by the low-affinity peptide. Finally, our results suggest that T cells possess a biochemical memory of previous stimulations of at least 1-2 days. We propose that the stability of T-cell-DC interactions, apart from their signaling potency, profoundly influences the robustness of T-cell activation. By offering the ability to control parameters that are difficult to manipulate experimentally, the virtual lymph node model provides new possibilities to tackle the fundamental mechanisms that regulate T-cell responses elicited by infections or vaccines.
MeSH term(s)	Animals ; Antigen Presentation/immunology ; Antigens/metabolism ; Cell Communication/immunology ; Cell Count ; Cell Proliferation ; Dendritic Cells/cytology ; Immunological Synapses/metabolism ; Lymph Nodes/immunology ; Lymphocyte Activation/immunology ; Mice, Inbred C57BL ; Mice, Transgenic ; Models, Biological ; Peptides/metabolism ; T-Lymphocytes/cytology ; T-Lymphocytes/immunology
Chemical Substances	Antigens ; Peptides
Language	English
Publishing date	2016-05-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	284057-1
ISSN	1440-1711 ; 0818-9641
ISSN (online)	1440-1711
ISSN	0818-9641
DOI	10.1038/icb.2016.36
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Article ; Online: On-lattice simulation of T cell motility, chemotaxis, and trafficking in the lymph node paracortex.

Bogle, Gib / Dunbar, P Rod

PloS one

2012 Volume 7, Issue 9, Page(s) e45258

Abstract: Agent-based simulation is a powerful method for investigating the complex interplay of the processes occurring in a lymph node during an adaptive immune response. We have previously established an agent-based modeling framework for the interactions ... ...

Abstract	Agent-based simulation is a powerful method for investigating the complex interplay of the processes occurring in a lymph node during an adaptive immune response. We have previously established an agent-based modeling framework for the interactions between T cells and dendritic cells within the paracortex of lymph nodes. This model simulates in three dimensions the "random-walk" T cell motility observed in vivo, so that cells interact in space and time as they process signals and commit to action such as proliferation. On-lattice treatment of cell motility allows large numbers of densely packed cells to be simulated, so that the low frequency of T cells capable of responding to a single antigen can be dealt with realistically. In this paper we build on this model by incorporating new numerical methods to address the crucial processes of T cell ingress and egress, and chemotaxis, within the lymph node. These methods enable simulation of the dramatic expansion and contraction of the T cell population in the lymph node paracortex during an immune response. They also provide a novel probabilistic method to simulate chemotaxis that will be generally useful in simulating other biological processes in which chemotaxis is an important feature.
MeSH term(s)	Adaptive Immunity ; Animals ; Antigens/immunology ; Cell Communication/immunology ; Chemotaxis/immunology ; Computer Simulation ; Dendritic Cells/cytology ; Dendritic Cells/immunology ; Humans ; Lymph Nodes/cytology ; Lymph Nodes/immunology ; Lymphocyte Activation ; Mice ; Models, Immunological ; Rats ; T-Lymphocytes/cytology ; T-Lymphocytes/immunology
Chemical Substances	Antigens
Language	English
Publishing date	2012-09-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0045258
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Article: Tissue Pharmacokinetic Properties and Bystander Potential of Hypoxia-Activated Prodrug CP-506 by Agent-Based Modelling.

Jackson-Patel, Victoria / Liu, Emily / Bull, Matthew R / Ashoorzadeh, Amir / Bogle, Gib / Wolfram, Anna / Hicks, Kevin O / Smaill, Jeff B / Patterson, Adam V

Frontiers in pharmacology

2022 Volume 13, Page(s) 803602

Abstract: Hypoxia-activated prodrugs are bioactivated in oxygen-deficient tumour regions and represent a novel strategy to exploit this pharmacological sanctuary for therapeutic gain. The approach relies on the selective metabolism of the prodrug under ... ...

Abstract	Hypoxia-activated prodrugs are bioactivated in oxygen-deficient tumour regions and represent a novel strategy to exploit this pharmacological sanctuary for therapeutic gain. The approach relies on the selective metabolism of the prodrug under pathological hypoxia to generate active metabolites with the potential to diffuse throughout the tumour microenvironment and potentiate cell killing by means of a "bystander effect". In the present study, we investigate the pharmacological properties of the nitrogen mustard prodrug CP-506 in tumour tissues using
Language	English
Publishing date	2022-02-08
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587355-6
ISSN	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2022.803602
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Article ; Online: T cell responses in lymph nodes.

Bogle, Gib / Dunbar, P Rod

Wiley interdisciplinary reviews. Systems biology and medicine

2010 Volume 2, Issue 1, Page(s) 107–116

Abstract: Activation of T cells by antigen-presenting cells (APCs) in lymph nodes (LNs) is a key initiating event in many immune responses. Our understanding of this process has been both improved and complicated in recent years by evidence from techniques such as ...

Abstract	Activation of T cells by antigen-presenting cells (APCs) in lymph nodes (LNs) is a key initiating event in many immune responses. Our understanding of this process has been both improved and complicated in recent years by evidence from techniques such as intravital microscopy that has revealed new levels of dynamism in the interaction of T cells and APCs. In particular, the complex motility of T cells within LNs, and their serial interactions with many APCs, imply that earlier static models of T cell activation need to be updated. Here we review the first attempts to model T cell interactions with APCs in LNs that incorporate simulations of T cell motility, based on experimental observations. We show that lattice-based modeling approaches are the dominant trend in these models, and then chart a possible course for development of these models toward spatially-resolved models of immune responses within LNs.
MeSH term(s)	Animals ; Antigen-Presenting Cells/immunology ; Cell Communication/immunology ; Cell Movement/immunology ; Cell Movement/physiology ; Computer Simulation ; Humans ; Lymph Nodes/immunology ; Lymphocyte Activation/physiology ; Models, Biological ; T-Lymphocytes/immunology ; T-Lymphocytes/physiology
Language	English
Publishing date	2010-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2503323-2
ISSN	1939-005X ; 1939-5094
ISSN (online)	1939-005X
ISSN	1939-5094
DOI	10.1002/wsbm.47
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Article ; Online: Radiosensitisation of SCCVII tumours and normal tissues in mice by the DNA-dependent protein kinase inhibitor AZD7648.

Hong, Cho R / Buckley, Chantal D / Wong, Way W / Anekal, Praju V / Dickson, Benjamin D / Bogle, Gib / Hicks, Kevin O / Hay, Michael P / Wilson, William R

Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology

2021 Volume 166, Page(s) 162–170

Abstract: Background and purpose: Inhibitors of DNA-dependent protein kinase (DNA-PK) are effective radiation sensitisers in preclinical tumours, but little is known about risks of normal tissue radiosensitisation. Here, we evaluate radiosensitisation of head and ...

Abstract	Background and purpose: Inhibitors of DNA-dependent protein kinase (DNA-PK) are effective radiation sensitisers in preclinical tumours, but little is known about risks of normal tissue radiosensitisation. Here, we evaluate radiosensitisation of head and neck squamous cell carcinoma (HNSCC) cells by DNA-PK inhibitor AZD7648 under oxia and anoxia in vitro, and tumour (SCCVII), oral mucosa and small intestine in mice. Materials and methods: Radiosensitisation of human (UT-SCC-54C) and murine (SCCVII) HNSCC cells by AZD7648 under oxia and anoxia was evaluated by clonogenic assay. Radiosensitisation of SCCVII tumours in C3H mice by oral AZD7648 (75 mg/kg) was determined by ex vivo clonogenic assay 3.5 days post-irradiation, with evaluation of normal tissue surrogate endpoints using 5-ethynyl-2'-deoxyuridine to facilitate detection of regenerating crypts in the ileum and repopulating S-phase cells in the ileum and oral mucosa of the same animals. Results: AZD7648 potently radiosensitised both cell lines, with similar sensitiser enhancement ratios for 10% survival (SER Conclusion: AZD7648 is a potent radiation sensitiser of both oxic and anoxic tumour cells, but also markedly radiosensitises stem cells in the small intestine and oral mucosa.
MeSH term(s)	Animals ; DNA ; DNA-Activated Protein Kinase ; Head and Neck Neoplasms/drug therapy ; Head and Neck Neoplasms/radiotherapy ; Humans ; Hypoxia ; Mice ; Mice, Inbred C3H ; Purines ; Pyrans ; Squamous Cell Carcinoma of Head and Neck/radiotherapy ; Triazoles
Chemical Substances	AZD7648 ; Purines ; Pyrans ; Triazoles ; DNA (9007-49-2) ; DNA-Activated Protein Kinase (EC 2.7.11.1)
Language	English
Publishing date	2021-11-30
Publishing country	Ireland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	605646-5
ISSN	1879-0887 ; 0167-8140
ISSN (online)	1879-0887
ISSN	0167-8140
DOI	10.1016/j.radonc.2021.11.027
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Article ; Online: Spatially-resolved pharmacokinetic/pharmacodynamic modelling of bystander effects of a nitrochloromethylbenzindoline hypoxia-activated prodrug.

Hong, Cho Rong / Mehta, Sunali Y / Liyanage, H D Sarath / McManaway, Sarah P / Lee, Ho H / Jaiswal, Jagdish K / Bogle, Gib / Tercel, Moana / Pruijn, Frederik B / Wilson, William R / Hicks, Kevin O

Cancer chemotherapy and pharmacology

2021 Volume 88, Issue 4, Page(s) 673–687

Abstract: Purpose: Hypoxia-activated prodrugs (HAPs) have the potential for eliminating chemo- and radiation-resistant hypoxic tumour cells, but their activity is often compromised by limited penetration into hypoxic zones. Nitrochloromethylbenzindoline (nitroCBI) ...

Abstract	Purpose: Hypoxia-activated prodrugs (HAPs) have the potential for eliminating chemo- and radiation-resistant hypoxic tumour cells, but their activity is often compromised by limited penetration into hypoxic zones. Nitrochloromethylbenzindoline (nitroCBI) HAPs are reduced in hypoxic cells to highly cytotoxic DNA minor groove alkylating aminoCBI metabolites. In this study, we investigate whether a lead nitroCBI, SN30548, generates a significant bystander effect through the diffusion of its aminoCBI metabolite and whether this compensates for any diffusion limitations of the prodrug in tumour tissue. Methods: Metabolism and uptake of the nitroCBI in oxic and anoxic cells, and diffusion through multicellular layer cultures, was characterised by LC-MS/MS. To quantify bystander effects, clonogenic cell killing of HCT116 cells was assessed in multicellular spheroid co-cultures comprising cells transfected with cytochrome P450 oxidoreductase (POR) or E. coli nitroreductase NfsA. Spatially-resolved pharmacokinetic/pharmacodynamic (PK/PD) models, parameterised by the above measurements, were developed for spheroids and tumours using agent-based and Green's function modelling, respectively. Results: NitroCBI was reduced to aminoCBI by POR under anoxia and by NfsA under oxia, and was the only significant cytotoxic metabolite in both cases. In spheroid co-cultures comprising 30% NfsA-expressing cells, non-metabolising cells were as sensitive as the NfsA cells, demonstrating a marked bystander effect. Agent-based PK/PD models provided good prediction of cytotoxicity in spheroids, while use of the same parameters in a Green's function model for a tumour microregion demonstrated that local diffusion of aminoCBI overcomes the penetration limitation of the prodrug. Conclusions: The nitroCBI HAP SN30548 generates a highly efficient bystander effect through local diffusion of its active metabolite in tumour tissue.
MeSH term(s)	Bystander Effect/drug effects ; Cell Hypoxia ; Chromatography, Liquid ; Coculture Techniques ; Escherichia coli Proteins/genetics ; HCT116 Cells ; Humans ; Indoles/pharmacokinetics ; Indoles/pharmacology ; Models, Biological ; NADPH-Ferrihemoprotein Reductase/genetics ; Nitroreductases/genetics ; Prodrugs ; Spheroids, Cellular/cytology ; Tandem Mass Spectrometry
Chemical Substances	Escherichia coli Proteins ; Indoles ; Prodrugs ; indoline (6DPT9AB2NK) ; NADPH-Ferrihemoprotein Reductase (EC 1.6.2.4) ; NfsA protein, E coli (EC 1.7.-) ; Nitroreductases (EC 1.7.-)
Language	English
Publishing date	2021-07-10
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	6820-2
ISSN	1432-0843 ; 0344-5704 ; 0943-9404
ISSN (online)	1432-0843
ISSN	0344-5704 ; 0943-9404
DOI	10.1007/s00280-021-04320-3
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Article ; Online: Agent-based simulation of T-cell activation and proliferation within a lymph node.

Bogle, Gib / Dunbar, P Rod

Immunology and cell biology

2009 Volume 88, Issue 2, Page(s) 172–179

Abstract: Recent intravital microscopy experiments have revealed the complex behavior of T cells within lymph nodes. Modeling T-cell responses in lymph nodes now requires integration of cell trafficking and motility with the molecular processes involved in T-cell ... ...

Abstract	Recent intravital microscopy experiments have revealed the complex behavior of T cells within lymph nodes. Modeling T-cell responses in lymph nodes now requires integration of cell trafficking and motility with the molecular processes involved in T-cell activation. We describe an agent-based model that allows such integration, in which T cells undertake a random walk through a three-dimensional representation of the lymph node paracortex, integrating signals from dendritic cells (DCs), and proliferating in response. The model accommodates simulation of a large number of T cells packed at realistic densities, and includes dynamic cell trafficking that allows the lymph nodes to swell and shrink as the immune response progresses. The results from the model, including the kinetics of cognate T-cell proliferation and release, and the changes in their avidity profile, are similar to those observed in vivo. We therefore propose that this modeling framework is capable of successfully simulating T-cell activation while also accounting for new spatiotemporal knowledge of how T cells and DCs interact. Although some of the parameters used to drive the model are not yet experimentally validated, the model is capable of testing the effects of alternative values for any parameter on the T-cell response. We intend to refine each aspect of the model in collaboration with both theoreticians and experimentalists.
MeSH term(s)	Animals ; Cell Proliferation ; Computer Simulation ; Dendritic Cells/cytology ; Dendritic Cells/immunology ; Lymph Nodes/cytology ; Lymph Nodes/immunology ; Lymphocyte Activation/immunology ; Lymphocyte Count ; Mice ; Models, Immunological ; T-Lymphocytes/cytology ; T-Lymphocytes/immunology ; Time Factors
Language	English
Publishing date	2009-11-03
Publishing country	United States
Document type	Journal Article
ZDB-ID	284057-1
ISSN	1440-1711 ; 0818-9641
ISSN (online)	1440-1711
ISSN	0818-9641
DOI	10.1038/icb.2009.78
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Article ; Online: High-resolution 3D imaging and topological mapping of the lymph node conduit system.

Kelch, Inken D / Bogle, Gib / Sands, Gregory B / Phillips, Anthony R J / LeGrice, Ian J / Dunbar, P Rod

PLoS biology

2019 Volume 17, Issue 12, Page(s) e3000486

Abstract: The conduit network is a hallmark of lymph node microanatomy, but lack of suitable imaging technology has prevented comprehensive investigation of its topology. We employed an extended-volume imaging system to capture the conduit network of an entire ... ...

Abstract	The conduit network is a hallmark of lymph node microanatomy, but lack of suitable imaging technology has prevented comprehensive investigation of its topology. We employed an extended-volume imaging system to capture the conduit network of an entire murine lymph node (comprising over 280,000 segments). The extensive 3D images provide a comprehensive overview of the regions supplied by conduits, including perivascular sleeves and distinctive "follicular reservoirs" within B cell follicles, surrounding follicular dendritic cells. A 3D topology map of conduits within the T-cell zone showed homogeneous branching, but conduit density was significantly higher in the superficial T-cell zone compared with the deep zone, where distances between segments are sufficient for T cells to lose contact with fibroblastic reticular cells. This topological mapping of the conduit anatomy can now aid modeling of its roles in lymph node function, as we demonstrate by simulating T-cell motility in the different T-cell zones.
MeSH term(s)	Animals ; B-Lymphocytes/immunology ; Cell Movement ; Fibroblasts ; Image Processing, Computer-Assisted/methods ; Imaging, Three-Dimensional/methods ; Lymph Nodes/diagnostic imaging ; Mice/immunology ; T-Lymphocytes/immunology
Language	English
Publishing date	2019-12-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2126776-5
ISSN	1545-7885 ; 1544-9173
ISSN (online)	1545-7885
ISSN	1544-9173
DOI	10.1371/journal.pbio.3000486
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