{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T17:41:26Z","timestamp":1787938886623,"version":"build-2784847793"},"reference-count":68,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,2,26]],"date-time":"2024-02-26T00:00:00Z","timestamp":1708905600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["23-71-10051"],"award-info":[{"award-number":["23-71-10051"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012190","name":"Ministry of Science and Higher Education of the Russian Federation","doi-asserted-by":"publisher","award":["075-10-2021-093, 075-15-2022-286"],"award-info":[{"award-number":["075-10-2021-093, 075-15-2022-286"]}],"id":[{"id":"10.13039\/501100012190","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>The thymus plays a central role in shaping human immune function. A mechanistic, quantitative description of immune cell dynamics and thymic output under homeostatic conditions and various patho-physiological scenarios are of particular interest in drug development applications, e.g., in the identification of potential therapeutic targets and selection of lead drug candidates against infectious diseases.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We here developed an integrative mathematical model of thymocyte dynamics in human. It incorporates mechanistic features of thymocyte homeostasis as well as spatial constraints of the thymus and considerations of age-dependent involution. All model parameter estimates were obtained based on published physiological data of thymocyte dynamics and thymus properties in mouse and human. We performed model sensitivity analyses to reveal potential therapeutic targets through an identification of processes critically affecting thymic function; we further explored differences in thymic function across healthy subjects, multiple sclerosis patients, and patients on fingolimod treatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found thymic function to be most impacted by the egress, proliferation, differentiation and death rates of those thymocytes which are most differentiated. Model predictions also showed that the clinically observed decrease in relapse risk with age, in multiple sclerosis patients who would have discontinued fingolimod therapy, can be explained mechanistically by decreased thymic output with age. Moreover, we quantified the effects of fingolimod treatment duration on thymic output.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>In summary, the proposed model accurately describes, in mechanistic terms, thymic output as a function of age. It may be further used to perform predictive simulations of clinically relevant scenarios which combine specific patho-physiological conditions and pharmacological interventions of interest.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2024.1321309","type":"journal-article","created":{"date-parts":[[2024,2,26]],"date-time":"2024-02-26T04:51:33Z","timestamp":1708923093000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["An integrative mechanistic model of thymocyte dynamics"],"prefix":"10.3389","volume":"15","author":[{"given":"Victoria","family":"Kulesh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirill","family":"Peskov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel","family":"Helmlinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gennady","family":"Bocharov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,2,26]]},"reference":[{"key":"B1","volume-title":"Kuby immunology","author":"Punt","year":"2019"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.26.021607.090408","article-title":"Thymus organogenesis","volume":"26","author":"Rodewald","year":"2008","journal-title":"Annu Rev Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1385\/IR:22:2-3:253","article-title":"The human thymus during aging","volume":"22","author":"Haynes","year":"2000","journal-title":"Immunol Res"},{"key":"B4","doi-asserted-by":"publisher","first-page":"437","DOI":"10.3390\/e23040437","article-title":"Modeling the dynamics of T-cell development in the thymus","volume":"23","author":"Robert","year":"2021","journal-title":"Entropy."},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.154.10.5103","article-title":"Cell expansion and growth arrest phases during the transition from precursor (CD4-8-) to immature (CD4+8+) thymocytes in normal and genetically modified mice","volume":"154","author":"P\u00e9nit","year":"1995","journal-title":"J Immunol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-3083.1985.tb01916.x","article-title":"The involution of the ageing human thymic epithelium is independent of puberty","volume":"22","author":"Steinmann","year":"1985","journal-title":"Scand J Immunol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2013.00316","article-title":"The effect of age on thymic function","volume":"4","author":"Palmer","year":"2013","journal-title":"Front Immunol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2009.04.003","article-title":"Thymic involution and immune reconstitution","volume":"30","author":"Lynch","year":"2009","journal-title":"Trends Immunol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1111\/imr.12418","article-title":"Thymus: the next (re)generation","volume":"271","author":"Chaudhry","year":"2016","journal-title":"Immunol Rev"},{"key":"B10","first-page":"497","article-title":"Involution patterns of the human thymus. I Size of the cortical area as a function of age","volume":"47","author":"Tosi","year":"1982","journal-title":"Clin Exp Immunol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtbi.2007.07.028","article-title":"T cell development in the thymus: From periodic seeding to constant output","volume":"249","author":"Cai","year":"2007","journal-title":"J Theor Biol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1303085","article-title":"Overlapping and asymmetric functions of TCR signaling during thymic selection of CD4 and CD8 lineages","volume":"192","author":"Sinclair","year":"2014","journal-title":"J Immunol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1016\/j.jtbi.2014.01.020","article-title":"Insights into the mechanisms of thymus involution and regeneration by modeling the glucocorticoid-induced perturbation of thymocyte populations dynamics","volume":"348","author":"Moleriu","year":"2014","journal-title":"J Theor Biol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2014.00019","article-title":"From pre-DP, post-DP, SP4, and SP8 Thymocyte Cell Counts to a Dynamical Model of Cortical and Medullary Selection","volume":"5","author":"Sawicka","year":"2014","journal-title":"Front Immunol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.168.10.4968","article-title":"Reevaluation of T cell receptor excision circles as a measure of human recent thymic emigrants","volume":"168","author":"Ye","year":"2002","journal-title":"J Immunol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.180.4.2240","article-title":"Comprehensive assessment and mathematical modeling of T cell population dynamics and homeostasis1","volume":"180","author":"Thomas-Vaslin","year":"2008","journal-title":"J Immunol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-10-184184","article-title":"Quantifying the development of the peripheral naive CD4+ T-cell pool in humans","volume":"113","author":"Bains","year":"2009","journal-title":"Blood."},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0900743","article-title":"Quantifying thymic export: combining models of naive T cell proliferation and TCR excision circle dynamics gives an explicit measure of thymic output","volume":"183","author":"Bains","year":"2009","journal-title":"J Immunol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"36159","DOI":"10.1038\/srep36159","article-title":"Modeling the development of the post-natal mouse thymus in the absence of bone marrow progenitors","volume":"6","author":"Zaharie","year":"2016","journal-title":"Sci Rep"},{"key":"B20","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1002\/psp4.12049","article-title":"Good practices in model-informed drug discovery and development: practice, application, and documentation","volume":"5","author":"Marshall","year":"2016","journal-title":"CPT Pharmacomet Syst Pharmacol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-022-03288-w","article-title":"Review: role of model-informed drug development approaches in the lifecycle of drug development and regulatory decision-making","volume":"39","author":"Madabushi","year":"2022","journal-title":"Pharm Res"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12388","article-title":"Tisagenlecleucel model-based cellular kinetic analysis of chimeric antigen receptor\u2013T cells","volume":"8","author":"Stein","year":"2019","journal-title":"CPT Pharmacomet Syst Pharmacol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/j.jtbi.2012.12.025","article-title":"Quantifying T lymphocyte turnover","volume":"327","author":"De Boer","year":"2013","journal-title":"J Theor Biol"},{"key":"B24","article-title":"The weight of the human thymus gland at necropsy","volume":"131","author":"Kendall","year":"1980","journal-title":"J Anat."},{"key":"B25","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1006\/cimm.1997.1148","article-title":"Phenotypic and immunohistological analyses of the human adult thymus: evidence for an active thymus during adult life","volume":"179","author":"Bertho","year":"1997","journal-title":"Cell Immunol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1126\/science.aay3224","article-title":"A cell atlas of human thymic development defines T cell repertoire formation","volume":"367","author":"Park","year":"2020","journal-title":"Science"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.164.12.6260","article-title":"Analysis of the human neonatal thymus: evidence for a transient thymic involution1","volume":"164","author":"Varas","year":"2000","journal-title":"J Immunol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.01659","article-title":"Conventional and computational flow cytometry analyses reveal sustained human intrathymic T cell development from birth until puberty","volume":"11","author":"Lavaert","year":"2020","journal-title":"Front Immunol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1006\/jsre.1998.5547","article-title":"Flow cytometric study of lymphocytes associated with thymoma and other thymic tumors","volume":"82","author":"Fujii","year":"1999","journal-title":"J Surg Res"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1006\/cimm.1993.1257","article-title":"Characterization of CD4+ Single positive cells that lack CD3 in the human thymus","volume":"151","author":"Takeuchi","year":"1993","journal-title":"Cell Immunol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2004.10.031","article-title":"Age-related changes in the cellular composition of the thymus in children","volume":"115","author":"Weerkamp","year":"2005","journal-title":"J Allergy Clin Immunol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)80056-4","article-title":"Generation of functional thymocytes in the human adult","volume":"10","author":"Jamieson","year":"1999","journal-title":"Immunity."},{"key":"B33","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1007\/s11357-010-9170-8","article-title":"Age-related deregulation of naive T cell homeostasis in elderly humans","volume":"33","author":"Ferrando-Mart\u00ednez","year":"2011","journal-title":"AGE."},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.164.4.2180","article-title":"Leukemia inhibitory factor, oncostatin M, IL-6, and stem cell factor mRNA expression in human thymus increases with age and is associated with thymic atrophy1","volume":"164","author":"Sempowski","year":"2000","journal-title":"J Immunol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1172\/JCI7558","article-title":"Analysis of the human thymic perivascular space during aging","volume":"104","author":"Flores","year":"1999","journal-title":"J Clin Invest."},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2016.10.007","article-title":"T cell development by the numbers","volume":"38","author":"Krueger","year":"2017","journal-title":"Trends Immunol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1007\/s00005-017-0503-5","article-title":"Thymus colonization: who, how, how many","volume":"66","author":"Krueger","year":"2018","journal-title":"Arch Immunol Ther Exp (Warsz)"},{"key":"B38","volume-title":"Fundamental immunology","author":"Paul","year":"2003"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.87.7.2579","article-title":"Kinetics of mature T-cell development in the thymus","volume":"87","author":"Egerton","year":"1990","journal-title":"Proc Natl Acad Sci"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1235","article-title":"Comparative biology of mouse versus human cells: modelling human cancer in mice","volume":"3","author":"Rangarajan","year":"2003","journal-title":"Nat Rev Cancer."},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2021.10.006","article-title":"Hematopoiesis in numbers","volume":"42","author":"Cosgrove","year":"2021","journal-title":"Trends Immunol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/2.6.501","article-title":"The kinetics of immature murine thymocyte development in vivo","volume":"2","author":"Egerton","year":"1990","journal-title":"Int Immunol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1038\/sj.gene.6363982","article-title":"Age-related thymic involution in C57BL\/6J \u00d7 DBA\/2J recombinant-inbred mice maps to mouse chromosomes 9 and 10","volume":"4","author":"Hsu","year":"2003","journal-title":"Genes Immun"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20070601","article-title":"Thymic emigration revisited","volume":"204","author":"McCaughtry","year":"2007","journal-title":"J Exp Med"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2014.00013","article-title":"Theories and quantification of thymic selection","volume":"5","author":"Yates","year":"2014","journal-title":"Front Immunol"},{"key":"B46","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1186\/s13073-021-00861-7","article-title":"Development of double-positive thymocytes at single-cell resolution","volume":"13","author":"Li","year":"2021","journal-title":"Genome Med"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12063","article-title":"Efficient generation and selection of virtual populations in quantitative systems pharmacology models","volume":"5","author":"Allen","year":"2016","journal-title":"CPT Pharmacomet Syst Pharmacol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtbi.2008.04.011","article-title":"A methodology for performing global uncertainty and sensitivity analysis in systems biology","volume":"254","author":"Marino","year":"2008","journal-title":"J Theor Biol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1900662","article-title":"Regulatory T cell development in the thymus","volume":"203","author":"Owen","year":"2019","journal-title":"J Immunol"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.643153","article-title":"Regulatory T cell heterogeneity in the thymus: impact on their functional activities","volume":"12","author":"Santamaria","year":"2021","journal-title":"Front Immunol"},{"key":"B51","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1111\/ajt.13456","article-title":"Discarded human thymus is a novel source of stable and long-lived therapeutic regulatory T cells","volume":"16","author":"Dijke","year":"2016","journal-title":"Am J Transplant."},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1177\/1352458514551456","article-title":"Newly produced T and B lymphocytes and T-cell receptor repertoire diversity are reduced in peripheral blood of fingolimod-treated multiple sclerosis patients","volume":"21","author":"Chiarini","year":"2015","journal-title":"Mult Scler J"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-019-09690-6","article-title":"Effects of disease-modifying therapy on peripheral leukocytes in patients with multiple sclerosis","volume":"268","author":"Schweitzer","year":"2021","journal-title":"J Neurol"},{"key":"B54","unstructured":"Gilenya\u2014product information"},{"key":"B55","unstructured":"Common Terminology Criteria for Adverse Events (CTCAE) v5.0"},{"key":"B56","article-title":"Biology: the unity and diversity of life","volume-title":"Books in the Brooks\/Cole biology series","author":"Starr","year":"1998"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2007.08.009","article-title":"Do most lymphocytes in humans really reside in the gut","volume":"28","author":"Ganusov","year":"2007","journal-title":"Trends Immunol"},{"key":"B58","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1208\/s12248-021-00585-x","article-title":"FDA-Industry Scientific Exchange on assessing quantitative systems pharmacology models in clinical drug development: a meeting report, summary of challenges\/gaps, and future perspective","volume":"23","author":"Bai","year":"2021","journal-title":"AAPS J"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.171.1.432","article-title":"Thymic export function and T cell homeostasis in patients with relapsing remitting multiple sclerosis1","volume":"171","author":"Hug","year":"2003","journal-title":"J Immunol"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2009.00451.x","article-title":"FTY720 (fingolimod) in Multiple Sclerosis: therapeutic effects in the immune and the central nervous system","volume":"158","author":"Brinkmann","year":"2009","journal-title":"Br J Pharmacol"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1038\/nature02284","article-title":"Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1","volume":"427","author":"Matloubian","year":"2004","journal-title":"Nature."},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/dxn023","article-title":"Modulation of T cell homeostasis and alloreactivity under continuous FTY720 exposure","volume":"20","author":"Metzler","year":"2008","journal-title":"Int Immunol"},{"key":"B63","doi-asserted-by":"publisher","first-page":"1317","DOI":"10.1136\/jnnp-2022-329607","article-title":"Rebound of clinical disease activity after fingolimod discontinuation? A nationwide cohort study of patients in Denmark","volume":"93","author":"Framke","year":"2022","journal-title":"J Neurol Neurosurg Amp Psychiatry"},{"key":"B64","doi-asserted-by":"publisher","first-page":"103278","DOI":"10.1016\/j.msard.2021.103278","article-title":"Factors associated with fingolimod rebound: A single center real-life experience","volume":"56","author":"Goncuoglu","year":"2021","journal-title":"Mult Scler Relat Disord"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1007\/s40120-019-00160-9","article-title":"Fingolimod rebound: A review of the clinical experience and management considerations","volume":"8","author":"Barry","year":"2019","journal-title":"Neurol Ther"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1023\/A:1009868929893","article-title":"The role of occam\u2019s razor in knowledge discovery","volume":"3","author":"Domingos","year":"1999","journal-title":"Data Min Knowl Discov"},{"key":"B67","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/j.jaut.2013.12.015","article-title":"Both Treg cells and Tconv cells are defective in the Myasthenia gravis thymus: Roles of IL-17 and TNF-\u03b1","volume":"52","author":"Gradolatto","year":"2014","journal-title":"Myasthenia Gravis Compr Rev"},{"key":"B68","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1038\/icb.2008.87","article-title":"Back to the thymus: peripheral T cells come home","volume":"87","author":"Hale","year":"2009","journal-title":"Immunol Cell Biol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2024.1321309\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,2,26]],"date-time":"2024-02-26T04:51:39Z","timestamp":1708923099000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2024.1321309\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,26]]},"references-count":68,"alternative-id":["10.3389\/fimmu.2024.1321309"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2024.1321309","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,26]]},"article-number":"1321309"}}