{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T03:56:42Z","timestamp":1792814202135,"version":"4.5.0"},"reference-count":38,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2013,5,14]],"date-time":"2013-05-14T00:00:00Z","timestamp":1368489600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2013,9]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Recent evidence suggests that functional deficiency in regulatory T cells (Tregs), an innate immunomodulator, exacerbates brain damage after cerebral ischemia. We therefore evaluated the effect of Treg transfer in rodent models of ischemic stroke and further investigated the mechanism underlying Treg\u2010afforded neuroprotection.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We examined the therapeutic potential of Tregs and the mechanisms of neuroprotection in vivo in 2 rodent models of ischemic stroke and in vitro in Treg\u2013neutrophil cocultures using a combined approach including cell\u2010specific depletion, gene knockout mice, and bone marrow chimeras.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Systemic administration of purified Tregs at 2, 6, or even 24 hours after middle cerebral artery occlusion resulted in a marked reduction of brain infarct and prolonged improvement of neurological functions lasting out to 4 weeks. Treg\u2010afforded neuroprotection was accompanied by attenuated blood\u2013brain barrier (BBB) disruption during early stages of ischemia, decreased cerebral inflammation, and reduced infiltration of peripheral inflammatory cells into the lesioned brain. Surprisingly, Tregs exerted early neuroprotection without penetrating into the brain parenchyma or inhibiting the activation of residential microglia. Rather, both in vivo and in vitro studies demonstrated that Tregs suppressed peripheral neutrophil\u2010derived matrix metallopeptidase\u20109 production, thus preventing proteolytic damage of the BBB. In addition to its potent central neuroprotection, Treg treatment was shown to ameliorate poststroke lymphopenia, suggesting a beneficial effect on immune status.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Our study suggests that Treg adoptive therapy is a novel and potent cell\u2010based therapy targeting poststroke inflammatory dysregulation and neurovascular disruption. Ann Neurol 2013;74:458\u2013471<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.23815","type":"journal-article","created":{"date-parts":[[2012,11,24]],"date-time":"2012-11-24T09:59:20Z","timestamp":1353751160000},"page":"458-471","source":"Crossref","is-referenced-by-count":277,"title":["Adoptive regulatory T\u2010cell therapy protects against cerebral ischemia"],"prefix":"10.1002","volume":"74","author":[{"given":"Peiying","family":"Li","sequence":"first","affiliation":[{"name":"Anesthesiology Department of Huashan Hospital State Key Laboratory of Medical Neurobiology and Institute of Brain Sciences Fudan University Shanghai China"},{"name":"Center of Cerebrovascular Disease Research University of Pittsburgh School of Medicine Pittsburgh PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Gan","sequence":"additional","affiliation":[{"name":"Center of Cerebrovascular Disease Research University of Pittsburgh School of Medicine Pittsburgh PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bao\u2010Liang","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Neurology and Key Laboratory of Cerebral Microcirculation University of Shandong Affiliated Hospital of Taishan Medical College Taian Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Anesthesiology Department of Huashan Hospital State Key Laboratory of Medical Neurobiology and Institute of Brain Sciences Fudan University Shanghai China"},{"name":"Center of Cerebrovascular Disease Research University of Pittsburgh School of Medicine Pittsburgh PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Binfeng","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Immunology University of Pittsburgh School of Medicine Pittsburgh 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