{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T18:24:45Z","timestamp":1779906285752,"version":"3.53.1"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2021,11,3]],"date-time":"2021-11-03T00:00:00Z","timestamp":1635897600000},"content-version":"vor","delay-in-days":545,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2020,5,7]],"date-time":"2020-05-07T00:00:00Z","timestamp":1588809600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2020,5,7]],"date-time":"2020-05-07T00:00:00Z","timestamp":1588809600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"name":"NIH 2T32","award":["GM0879201-11A1"],"award-info":[{"award-number":["GM0879201-11A1"]}]},{"name":"NIH 2T32","award":["GM0879201-11A1"],"award-info":[{"award-number":["GM0879201-11A1"]}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2020,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Traumatic brain injury (TBI) causes a profound inflammatory response within the central nervous system and peripheral immune system, which contributes to secondary brain injury and further morbidity and mortality. Preclinical investigations have demonstrated that treatments that downregulate microglia activation and polarize them toward a reparative\/anti-inflammatory phenotype have improved outcomes in preclinical models. However, no therapy to date has translated into proven benefits in human patients. Regulatory T cells (Treg) have been shown to downregulate pathologic immune responses of the innate and adaptive immune system across a variety of pathologies. Furthermore, cellular therapy has been shown to augment host Treg responses in preclinical models; yet, studies investigating the use of Treg as a therapeutic for TBI are lacking. In a rodent TBI model, we demonstrate that human umbilical cord blood Treg modulate the central and peripheral immune response after injury in vitro and in vivo.<\/jats:p>\n               <jats:sec>\n                  <jats:title\/>\n                  <jats:p>Significance statement This study demonstrates that human regulatory T cells (Treg) expanded from umbilical cord blood can reduce neuroinflammation associated with traumatic brain injury. A single dose of Treg can cause long-term changes in brain microgliosis in chronic TBI.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1002\/sctm.19-0444","type":"journal-article","created":{"date-parts":[[2020,5,8]],"date-time":"2020-05-08T06:25:41Z","timestamp":1588919141000},"page":"903-916","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Human cord blood-derived regulatory T-cell therapy modulates the central and peripheral immune response after traumatic brain injury"],"prefix":"10.1093","volume":"9","author":[{"given":"Henry W.","family":"Caplan","sequence":"first","affiliation":[{"name":"Department of Pediatric Surgery, McGovern Medical School University of Texas Health Science Center at Houston, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karthik S.","family":"Prabhakara","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, McGovern Medical School University of Texas Health Science Center at Houston, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akshita","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, McGovern Medical School University of Texas Health Science Center at Houston, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naama E.","family":"Toledano-Furman","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, McGovern Medical School University of Texas Health Science Center at Houston, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia","family":"Martin","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, McGovern Medical School University of Texas Health Science Center at Houston, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louis","family":"Carrillo","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, McGovern Medical School University of Texas Health Science Center at Houston, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas F.","family":"Moreno","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, McGovern Medical School University of Texas Health Science Center at Houston, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea S.","family":"Bordt","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, McGovern Medical School University of Texas Health Science Center at Houston, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott D.","family":"Olson","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, McGovern Medical School University of Texas Health Science Center at Houston, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"Charles S.","family":"Cox","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, McGovern Medical School University of Texas Health Science Center at Houston, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,5,7]]},"reference":[{"key":"2022022809324737400_sct312706-bib-0001","volume-title":"Traumatic Brain Injury in the United States","author":"Faul","year":"2010"},{"key":"2022022809324737400_sct312706-bib-0002","volume-title":"Report to Congress on Traumatic Brain Injury in the United States: Epidemiology and Rehabilitation","author":"Centers for Disease Control and Prevention","year":"2015"},{"issue":"3","key":"2022022809324737400_sct312706-bib-0003","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1038\/nrneurol.2017.13","article-title":"The far-reaching scope of neuroinflammation after traumatic brain injury","volume":"13","author":"Simon","year":"2017","journal-title":"Nat Rev Neurol"},{"issue":"4","key":"2022022809324737400_sct312706-bib-0004","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1016\/j.neuroscience.2004.06.046","article-title":"Edema and brain trauma","volume":"129","author":"Unterberg","year":"2004","journal-title":"Neuroscience"},{"issue":"8","key":"2022022809324737400_sct312706-bib-0005","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1016\/j.bbi.2012.06.008","article-title":"Neuroinflammation after traumatic brain injury: opportunities for therapeutic intervention","volume":"26","author":"Kumar","year":"2012","journal-title":"Brain Behav Immun"},{"issue":"1","key":"2022022809324737400_sct312706-bib-0006","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1186\/s12974-018-1122-8","article-title":"Therapeutic time window of multipotent adult progenitor therapy after traumatic brain injury","volume":"15","author":"Bedi","year":"2018","journal-title":"J Neuroinflammation"},{"issue":"12","key":"2022022809324737400_sct312706-bib-0007","doi-asserted-by":"crossref","first-page":"953","DOI":"10.5966\/sctm.2013-0100","article-title":"Intravenous multipotent adult progenitor cell therapy attenuates activated microglial\/macrophage response and improves spatial learning after traumatic brain injury","volume":"2","author":"Bedi","year":"2013","journal-title":"Stem Cells Translational Medicine"},{"key":"2022022809324737400_sct312706-bib-0008","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.jss.2017.02.078","article-title":"Preclinical progenitor cell therapy in traumatic brain injury: a meta-analysis","volume":"214","author":"Jackson","year":"2017","journal-title":"J Surg Res"},{"key":"2022022809324737400_sct312706-bib-0009","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1186\/1742-2094-9-228","article-title":"Intravenous multipotent adult progenitor cell therapy after traumatic brain injury: modulation of the resident microglia population","volume":"9","author":"Walker","year":"2012","journal-title":"J Neuroinflammation"},{"issue":"10","key":"2022022809324737400_sct312706-bib-0010","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1093\/intimm\/dxp095","article-title":"Regulatory T cells: how do they suppress immune responses?","volume":"21","author":"Sakaguchi","year":"2009","journal-title":"Int Immunol"},{"key":"2022022809324737400_sct312706-bib-0011","doi-asserted-by":"crossref","first-page":"1578","DOI":"10.3389\/fimmu.2017.01578","article-title":"Tregs: where we are and what comes next?","volume":"8","author":"Zhao","year":"2017","journal-title":"Front Immunol"},{"issue":"5","key":"2022022809324737400_sct312706-bib-0012","doi-asserted-by":"crossref","first-page":"1416","DOI":"10.1002\/stem.2603","article-title":"Prostaglandin E2 indicates therapeutic efficacy of mesenchymal stem cells in experimental traumatic brain injury","volume":"35","author":"Kota","year":"2017","journal-title":"Stem Cells"},{"issue":"1","key":"2022022809324737400_sct312706-bib-0013","doi-asserted-by":"crossref","first-page":"33","DOI":"10.5966\/sctm.2015-0065","article-title":"Propranolol and mesenchymal stromal cells combine to treat traumatic brain injury","volume":"5","author":"Kota","year":"2016","journal-title":"Stem Cells Trans Med"},{"issue":"2","key":"2022022809324737400_sct312706-bib-0014","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1016\/j.expneurol.2010.07.005","article-title":"Intravenous multipotent adult progenitor cell therapy for traumatic brain injury: preserving the blood brain barrier via an interaction with splenocytes","volume":"225","author":"Walker","year":"2010","journal-title":"Exp Neurol"},{"key":"2022022809324737400_sct312706-bib-0015","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1007\/978-1-4939-8564-7_12","volume-title":"Pre-Clinical and Clinical Methods in Brain Trauma Research","author":"Toledano Furman","year":"2018"},{"issue":"1","key":"2022022809324737400_sct312706-bib-0016","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1089\/neu.1988.5.1","article-title":"Controlled cortical impact: a new experimental brain injury model","volume":"5","author":"Lighthall","year":"1988","journal-title":"J Neurotrauma"},{"issue":"9","key":"2022022809324737400_sct312706-bib-0017","doi-asserted-by":"crossref","first-page":"2152","DOI":"10.1016\/j.ymthe.2018.06.022","article-title":"Teriflunomide modulates vascular permeability and microglial activation after experimental traumatic brain injury","volume":"26","author":"Prabhakara","year":"2018","journal-title":"Mol Ther"},{"issue":"2","key":"2022022809324737400_sct312706-bib-0018","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1016\/j.jss.2014.05.011","article-title":"Far-red tracer analysis of traumatic cerebrovascular permeability","volume":"190","author":"Liao","year":"2014","journal-title":"J Surg Res"},{"issue":"2","key":"2022022809324737400_sct312706-bib-0019","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1002\/cyto.a.23267","article-title":"OMIP-041: Optimized multicolor immunofluorescence panel rat microglial staining protocol","volume":"93","author":"Toledano Furman","year":"2018","journal-title":"Cytometry A"},{"issue":"4","key":"2022022809324737400_sct312706-bib-0020","doi-asserted-by":"crossref","first-page":"295","DOI":"10.2217\/rme-2018-0106","article-title":"Human umbilical cord blood cells restore vascular integrity in injured rat brain and modulate inflammation in vitro","volume":"14","author":"Srivastava","year":"2019","journal-title":"Regen Med"},{"issue":"6","key":"2022022809324737400_sct312706-bib-0021","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1038\/nbt.2594","article-title":"viSNE enables visualization of high dimensional single-cell data and reveals phenotypic heterogeneity of leukemia","volume":"31","author":"Amir el","year":"2013","journal-title":"Nat Biotechnol"},{"key":"2022022809324737400_sct312706-bib-0022","first-page":"2579","article-title":"Visualizing Data using t-SNE","volume":"9","author":"Maaten","year":"2008","journal-title":"J Mach Learn Res"},{"issue":"1","key":"2022022809324737400_sct312706-bib-0023","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1002\/eji.201545774","article-title":"The end of gating? An introduction to automated analysis of high dimensional cytometry data","volume":"46","author":"Mair","year":"2016","journal-title":"Eur J Immunol"},{"issue":"13","key":"2022022809324737400_sct312706-bib-0024","doi-asserted-by":"crossref","first-page":"1419","DOI":"10.1089\/neu.2017.5399","article-title":"Chronic alterations in systemic immune function after traumatic brain injury","volume":"35","author":"Ritzel","year":"2018","journal-title":"J Neurotrauma"},{"issue":"10","key":"2022022809324737400_sct312706-bib-0025","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1038\/nrn1765","article-title":"Central nervous system injury-induced immune deficiency syndrome","volume":"6","author":"Meisel","year":"2005","journal-title":"Nat Rev Neurosci"},{"key":"2022022809324737400_sct312706-bib-0026","doi-asserted-by":"crossref","first-page":"556","DOI":"10.3389\/fimmu.2016.00556","article-title":"Emerging roles for the immune system in traumatic brain injury","volume":"7","author":"McKee","year":"2016","journal-title":"Front Immunol"},{"issue":"7","key":"2022022809324737400_sct312706-bib-0027","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0041892","article-title":"Temporal changes in cell marker expression and cellular infiltration in a controlled cortical impact model in adult male C57BL\/6 mice","volume":"7","author":"Jin","year":"2012","journal-title":"PLoS One"},{"key":"2022022809324737400_sct312706-bib-0028","doi-asserted-by":"crossref","first-page":"1707","DOI":"10.12659\/MSM.901124","article-title":"Long-term kinetics of immunologic components and neurological deficits in rats following repetitive mild traumatic brain injury","volume":"23","author":"Bai","year":"2017","journal-title":"Med Sci Monit"},{"issue":"1","key":"2022022809324737400_sct312706-bib-0029","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1186\/s12974-019-1550-0","article-title":"Depletion of regulatory T cells increases T cell brain infiltration, reactive astrogliosis, and interferon-gamma gene expression in acute experimental traumatic brain injury","volume":"16","author":"Kramer","year":"2019","journal-title":"J Neuroinflammation"},{"issue":"3","key":"2022022809324737400_sct312706-bib-0030","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1002\/ana.22455","article-title":"Inflammation after trauma: microglial activation and traumatic brain injury","volume":"70","author":"Ramlackhansingh","year":"2011","journal-title":"Ann Neurol"},{"issue":"1","key":"2022022809324737400_sct312706-bib-0031","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1097\/NEN.0000000000000021","article-title":"Progressive neurodegeneration after experimental brain trauma: association with chronic microglial activation","volume":"73","author":"Loane","year":"2014","journal-title":"J Neuropathol Exp Neurol"},{"issue":"Pt 1","key":"2022022809324737400_sct312706-bib-0032","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1093\/brain\/aws322","article-title":"Inflammation and white matter degeneration persist for years after a single traumatic brain injury","volume":"136","author":"Johnson","year":"2013","journal-title":"Brain"},{"issue":"2","key":"2022022809324737400_sct312706-bib-0033","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1038\/mp.2017.246","article-title":"Markers of microglia in post-mortem brain samples from patients with Alzheimer's disease: a systematic review","volume":"23","author":"Hopperton","year":"2018","journal-title":"Mol Psychiatry"},{"issue":"10","key":"2022022809324737400_sct312706-bib-0034","doi-asserted-by":"crossref","first-page":"1506","DOI":"10.1002\/glia.22370","article-title":"Phenotyping primary human microglia: tight regulation of LPS responsiveness","volume":"60","author":"Melief","year":"2012","journal-title":"Glia"},{"key":"2022022809324737400_sct312706-bib-0035","doi-asserted-by":"crossref","first-page":"1866","DOI":"10.3389\/fimmu.2017.01866","article-title":"\u03b22 Integrins as regulators of dendritic cell, monocyte, and macrophage function","volume":"8","author":"Schittenhelm","year":"2017","journal-title":"Front Immunol"},{"key":"2022022809324737400_sct312706-bib-0036","doi-asserted-by":"crossref","first-page":"464","DOI":"10.3389\/fimmu.2019.00464","article-title":"The human FcgammaRII (CD32) family of leukocyte FcR in health and disease","volume":"10","author":"Anania","year":"2019","journal-title":"Front Immunol"},{"issue":"1","key":"2022022809324737400_sct312706-bib-0037","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1111\/nan.12011","article-title":"Review: activation patterns of microglia and their identification in the human brain","volume":"39","author":"Boche","year":"2013","journal-title":"Neuropathol Appl Neurobiol"},{"issue":"6","key":"2022022809324737400_sct312706-bib-0038","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1080\/13550280290100941","article-title":"Regulation and function of class II major histocompatibility complex, CD40, and B7 expression in macrophages and microglia: implications in neurological diseases","volume":"8","author":"O'Keefe","year":"2002","journal-title":"J Neurovirol"},{"issue":"1","key":"2022022809324737400_sct312706-bib-0039","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1186\/s13195-015-0139-9","article-title":"Immune phenotypes of microglia in human neurodegenerative disease: challenges to detecting microglial polarization in human brains","volume":"7","author":"Walker","year":"2015","journal-title":"Alzheimers Res Ther"},{"issue":"8","key":"2022022809324737400_sct312706-bib-0040","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1038\/nn.4338","article-title":"A polarizing question: do M1 and M2 microglia exist?","volume":"19","author":"Ransohoff","year":"2016","journal-title":"Nat Neurosci"},{"issue":"3","key":"2022022809324737400_sct312706-bib-0041","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1016\/j.celrep.2019.09.013","article-title":"TET2 regulates the neuroinflammatory response in microglia","volume":"29","author":"Carrillo-Jimenez","year":"2019","journal-title":"Cell Rep"},{"key":"2022022809324737400_sct312706-bib-0042","doi-asserted-by":"crossref","first-page":"307","DOI":"10.3389\/fncel.2019.00307","article-title":"Time-dependent changes in microglia transcriptional networks following traumatic brain injury","volume":"13","author":"Izzy","year":"2019","journal-title":"Front Cell Neurosci"}],"container-title":["Stem Cells Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fsctm.19-0444","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/sctm.19-0444","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/sctm.19-0444","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/stcltm\/article-pdf\/9\/8\/903\/42628853\/stcltm_9_8_903.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/stcltm\/article-pdf\/9\/8\/903\/42628853\/stcltm_9_8_903.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,28]],"date-time":"2022-02-28T09:43:24Z","timestamp":1646041404000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/stcltm\/article\/9\/8\/903\/6406893"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5,7]]},"references-count":42,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2020,5,7]]},"published-print":{"date-parts":[[2020,8,1]]}},"URL":"https:\/\/doi.org\/10.1002\/sctm.19-0444","relation":{},"ISSN":["2157-6564","2157-6580"],"issn-type":[{"value":"2157-6564","type":"print"},{"value":"2157-6580","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2020,8,1]]},"published":{"date-parts":[[2020,5,7]]},"assertion":[{"value":"2019-12-21","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-04-04","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-05-07","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}