title: Adoptive regulatory T-cell therapy protects against cerebral ischemia.
abstract: OBJECTIVE
  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-afforded neuroprotection.
  
  
  METHODS
  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-neutrophil cocultures using a combined approach including cell-specific depletion, gene knockout mice, and bone marrow chimeras.
  
  
  RESULTS
  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-afforded neuroprotection was accompanied by attenuated blood-brain 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-derived matrix metallopeptidase-9 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.
  
  
  CONCLUSIONS
  Our study suggests that Treg adoptive therapy is a novel and potent cell-based therapy targeting poststroke inflammatory dysregulation and neurovascular disruption.
authors.affiliation: Anesthesiology Department of Huashan Hospital, State Key Laboratory of Medical Neurobiology and Institute of Brain Sciences, Fudan University, Shanghai, China; Center of Cerebrovascular Disease Research, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: Peiying
authors.initials: P
authors.lastname: Li
authors.forename: Yu
authors.initials: Y
authors.lastname: Gan
authors.forename: Bao-Liang
authors.initials: BL
authors.lastname: Sun
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.forename: Binfeng
authors.initials: B
authors.lastname: Lu
authors.forename: Yanqin
authors.initials: Y
authors.lastname: Gao
authors.forename: Weimin
authors.initials: W
authors.lastname: Liang
authors.forename: Angus W
authors.initials: AW
authors.lastname: Thomson
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Hu
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000276:immunology* / Q000503:physiopathology; D001921:Brain / Q000276:immunology* / Q000503:physiopathology; D002545:Brain Ischemia / Q000276:immunology / Q000503:physiopathology / Q000628:therapy*; D004195:Disease Models, Animal; D051379:Mice; D018345:Mice, Knockout; D020521:Stroke / Q000276:immunology / Q000503:physiopathology / Q000628:therapy*; D050378:T-Lymphocytes, Regulatory / Q000637:transplantation*; D013997:Time Factors