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   Immunobiology models: Fibrosis and Lymph Node Cellular Dynamics

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Stephanie Evans, J. Russell Butler, Joshua T. Mattila, Denise E. Kirschner, Systems biology predicts that fibrosis in tuberculous granulomas may arise through macrophage-to-myofibroblast transformation, PLoS Computational Biology (2020), DOI: 10.1371/journal.pcbi.1008520, PMID: 33370784, PMCID: 7793262

Julie Leonard-Duke, Stephanie Evans, Riley T. Hannan, Thomas H. Barker, Jason H.T. Bates, Catherine A. Bonham, Bethany B. Moore, Denise E. Kirschner, and Shayn M. Peirce, Multi-scale models of lung fibrosis, Matrix Biology, Available online 11 May 2020, In Press, DOI: 10.1016/j.matbio.2020.04.003, PMID: 32438056, PMCID: (pending),

Hayley C. Warsinske, Amanda K. Wheaton, Kevin K. Kim, Jennifer J. Linderman, Bethany B. Moore, and Denise E. Kirschner, Computational Modeling Predicts Simultaneous Targeting of Fibroblasts and Epithelial Cells Is Necessary for Treatment of Pulmonary Fibrosis, Front. Pharmacol., 23 June 2016, DOI: 10.3389/fphar.2016.00183, PMID: 27445819, PMCID: 4917547.

Warsinske, Hayley C., Ashley, Shanna L., Linderman, Jennifer J., Moore, Bethany B., Kirschner, Denise E., Identifying Mechanisms of Homeostatic Signaling in Fibroblast Differentiation, Bulletin of Mathematical Biology, Sep, 2015, Springer US, DOI: 10.1007/s11538-015-0096-2, PMID: 26384829, PMCID: 4637267.

Cilfone, N, Kirschner, D and Linderman, JJ. Strategies for Efficient numerical implementation of hybrid multi-scale agent-based models to describe biological systems, Cellular and Molecular Bioengineering, Nov, 2014, DOI: 10.1007/s12195-014-0363-6, PMID: 26366228, PMCID: 4564133

Chang Gong, Jennifer J. Linderman, Denise Kirschner, Harnessing the heterogeneity of T cell differentiation fate to fine-tune generation of effector and memory T cells, Front. Immunol. 5:57, 2014, DOI: 10.3389/fimmu.2014.00057, PMID: 24600448, PMCID: 3928592

This article was one of the most viewed Frontiers in Immunology research articles in February 2014!
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Chang Gong, Joshua T. Mattila, Mark Miller, JoAnne L. Flynn, Jennifer J. Linderman, D. Kirschner, Predicting lymph node output efficiency through systems biology, Journal of Theoretical Biology, Volume 335, October 21 2013, Pages 169-184, ePUB: June 29, 2013, DOI: 10.1016/j.jtbi.2013.06.016, PMID: 23816876, PMCID: 3783027

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Henry P. Mirsky, Mark J. Miller, Jennifer J. Linderman, Denise E. Kirschner, Systems biology approaches for understanding cellular mechanisms of immunity in lymph nodes during infection, Journal of Theoretical Biology, Oct 21, 2011, 287:160-70, ISSN 0022-5193, DOI: 10.1016/j.jtbi.2011.06.037, PMID: 21798267, PMCID: 4504675

Jennifer J. Linderman, Thomas Riggs, Manjusha Pande, Mark Miller, Simeone Marino, and Denise E. Kirschner, Characterizing the Dynamics of CD4+ T Cell Priming within a Lymph Node. Journal of Immunology, 2010, 184: pp 2873-2885, DOI: 10.4049/jimmunol.0903117, PMID: 20154206, PMCID: 3153313

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Denise E. Kirschner and Jennifer J. Linderman, Mathematical and computational approaches can complement experimental studies of host pathogen interactions. Cellular Microbiology (2009) 11(4), DOI: 10.1111/j.1462-5822.2009.01281.x, PMID: 19134115, PMCID: 2720090

Thomas Riggs, Adrienne Walts, Nicolas Perry, Laura Bickle, Jennifer N. Lynch, Amy Myers, Joanne Flynn, Jennifer J. Linderman, Mark J. Miller, Denise E. Kirschner, A comparison of random vs. chemotaxis driven contacts of T cells with dendritic cells during repertoire scanning , Journal of Theoretical Biology (2007), DOI: 10.1016/j.jtbi.2007.10.015, PMID: 18068193, PMCID: 2548315

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Martin J. Blaser, Denise Kirschner, The equilibria that allow bacterial persistence in human hosts , Nature, Vol 449, j18, October 2007, pp 483-489, DOI: 10.1038/nature06198, PMID: 17943121, PMCID: (exempt)

Niyaz Ahmed, of the Pathogen Evolution Laboratory, Centre for DNA Fingerprinting and Diagnostics, India, gives his comments on the article at
This is a provocative yet legitimate proposal on how pathogenic bacteria adapt to their co-evolved hosts across a wide array of conditions linked to biology of both the host and pathogen, over huge evolutionary timescales. The authors focus on the concept that persistence represents finely negotiated, well balanced host- microbial interests, culminating in a long-term equilibrium whose maintenance requires a series of evolved, nested equilibria leading to the overall homeostasis. To support their assumption the authors harness observed pathobiology of three dreaded pathogens (H. pylori, S. typhi and M. tuberculosis). Based on the fact that genomic and biological features of these 'specialist' bacteria are quite diverse, authors generalize their model for other pathogens as well. If it is so, this model may also fit to commensals and other 'generalist' bacteria who might have accompanied humans in various capacities throughout their association. This dogma may therefore be relevant in understanding acquisition and/or attenuation of virulence with the change in human history and ecology. Although this is a largely speculative treatise, I am sure it will provide a foundation for future experimental evidence.
Raymond Mejia, of the National Heart, Lung and Blood Institute (NHLBI), and the National Institutes of Health (NIH), gives his comments on the article at
This study uses a mathematical model to explain bacterial persistence in a host population. Symbiosis is characterized by existence of evolutionary stable states that permit homeostasis. The model is applied to three bacteria with human hosts, H. pylori, S. typhi, and M. tuberculosis, and can be utilized to investigate how virulence may vary with changes in human ecology.

Denise E. Kirschner, Stewart T. Chang, Thomas W. Riggs, Nicolas Perry, Jennifer J. Linderman, Toward a multi scale model of antigen presentation in immunity, Immunological Reviews 2007 Vol. 216:,pp. 93-118, PMID: n/a, PMCID: n/a, NIHMSID: n/a

Simeone Marino, Edoardo Beretta, and Denise E. Kirschner The Role of Delays in Innate and Adaptive Immunity to Intracellular Bacterial Infection, Mathematical BioSciences and Engineering, Volume 4, Number 2, April 2007, pp. 261-286, PMID: 17658927, PMCID: (exempt).

Edoardo Beretta, Margherita Carletti, Denise E. Kirschner, and Simeone Marino Stability Analysis of a Mathematical Model of the Immune Response with Delays, 177-206, Mathematics for Life Science and Medicine, Springer-Verlag Berlin Heidelberg, 2007, PMID: n/a, PMCID: (exempt).

Denise Kirschner, The Multi-scale Immune Response to Pathogens: M. tuberculosis as an Example, In Silico Immunology, Springer US, pp. 289-311, 2007, DOI: 10.1007/978-0-387-39241-7, PMID: n/a, PMCID: (exempt).

Penelope A. Morel, Shlomo Ta'asan, Benoit F. Morel, Denise E. Kirschner, and Joanne L. Flynn New Insights into Mathematical Modeling of the Immune System , Immunologic Research, Vol. 36, Issue 1-3, pp:157-165, 2006, PMID: 17337776, PMCID: n/a, NIHMSID: n/a.

Chang, ST, Ghosh, D, Kirschner, D and Linderman, JL. Peptide length-based prediction of peptide-MHC class II binding. , Bioinformatics, 22:2761-2767, 2006, PMID: 17000752, PMCID: n/a, NIHMSID: n/a.

J. Christian J Ray and Kirschner. D. Requirement for multiple activation signals by anti-inflammatory feedback in macrophages , Journal of Theoretical Biology , 241(2), pp. 276-294. 2006, PMID: 16460764, PMCID: n/a, NIHMSID: n/a.

Segovia-Juarez, J, S. Colombano, Kirschner, D Identifying DNA splice sites using hypernetworks with artificial molecular evolution , Biosystems, Volume 87, February 2007, Pages 117-124, PMID: 17116361, PMCID: n/a, NIHMSID: n/a.

Stewart T. Chang, Jennifer J. Linderman, and Denise E. Kirschner Multiple mechanisms allow Mycobacterium tuberculosis to continuously inhibit MHC class II-mediated antigen presentation by macrophages , with supporting text, 4530 4535 PNAS March 22, 2005 vol. 102 no. 12, PMID: 15767567, PMCID: PMC555518, NIHMSID: n/a.

Simeone Marino, Suman Ganguli, Ian Joseph, and Denise Kirschner The Importance of an Inter-compartmental Delay in a Model for Human Gastric Acid Secretion , Bulletin of Mathematical Biology (2003) 00, 1-28, PMID: 14607284, PMCID: n/a, NIHMSID: n/a.

Ping Ye and Denise E. Kirschner Measuring Emigration of Human Thymocytes by T-Cell Receptor Excision Circles. Critical Reviews in Immunology, 22(5&6):483 498 (2002), PMID: 12803323, PMCID: n/a, NIHMSID: n/a.

Ping Ye and Denise E. Kirschner, Reevaluation of T Cell Receptor Excision Circles as a Measure of Human Revent Thymic Emigrants J. Immunology 168, 10, 2002, PMID: 11994448, PMCID: n/a, NIHMSID: n/a.

Denise E. Kirschner, Reconstructing Microbial Pathogenesis ASM News Vol 67, Numer 11, 2001, PMID: n/a, PMCID: n/a, NIHMSID: n/a.

Jorge X. Velasco-Hernandez, Jose A. Garcia, Denise E. Kirschner , Remarks on Modeling Host-Viral Dynamics and Treatment. in: Volume 125: Mathematical Approaches for Emerging and Reemerging Infectious Diseases Part I: An Introduction to Models, Methods, and Theory
Editors: Carlos Castillo-Chavez with Sally Blower, Pauline van den Driessche, Denise Kirschner, and Abdul-Aziz Yakubu, 2001, PMID: n/a, PMCID: n/a, NIHMSID: n/a.

Wigginton J and Kirschner D. A model of cellular immune regulation in infection with Mycobacterium tuberculosis, Journal of Immunology, Feb 2001, PMID: 11160244, PMCID: n/a, NIHMSID: n/a.

Kirschner D, Webb GF and Cloyd M. A model of HIV-1 disease progression based on virus-induced lymph node homing and homing-induced apoptosis of CD4+ T lymphocytes. J. AIDS & Human Retrov vol 23, pps. , August 2000, PMID: 11015152, PMCID: n/a, NIHMSID: n/a.

Covert D and Kirschner D. Revisiting the early models of the host-pathogen interactions in HIV infection, Comments on Theoretical Biology Vol 5(6) pp. 383-411, 2000, PMID: n/a, PMCID: n/a, NIHMSID: n/a.

Blaser MJ and Kirschner D. Dynamics of Helicobacter pylori colonization in relation to the host immune response. PNAS, 96:8359-8364, 1999, PMID: 10411880, PMCID: PMC17522, NIHMSID: n/a.

Kirschner D and Panetta JC. Modeling immunotherapy of the tumor-immune interaction. J Math Biol, 37: 235-252, 1998, PMID: 9785481, PMCID: n/a, NIHMSID: n/a.

Kirschner D and Webb GF. Immunotherapy of HIV-1 infection. J Biol Systems, 6:71-83, 1998, PMID: n/a, PMCID: n/a, NIHMSID: n/a.

Kirschner D, Mehr R and Perelson A. The role of the thymus in pediatric HIV-1 infection. J AIDS & Human Retrov, 18:95-109, 1998, PMID: 9637574, PMCID: n/a, NIHMSID: n/a.

Kirschner D and Webb GF. A model for treatment strategy in the chemotherapy of AIDS. Bull Math Biol 58:367-390, 1996, PMID: 8713663, PMCID: n/a, NIHMSID: n/a.

Perelson A, Kirschner D, De Boer R. The dynamics of HIV infection of CD4+ T cells. Math Biosci 114:81-125, 1993, PMID: 11517319, PMCID: PMC56941, NIHMSID: n/a.


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