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Adoptive regulatory T‐cell therapy protects against cerebral ischemia
Author(s) -
Li Peiying,
Gan Yu,
Sun BaoLiang,
Zhang Feng,
Lu Binfeng,
Gao Yanqin,
Liang Weimin,
Thomson Angus W.,
Chen Jun,
Hu Xiaoming
Publication year - 2013
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.23815
Subject(s) - neuroprotection , medicine , microglia , ischemia , in vivo , blood–brain barrier , adoptive cell transfer , inflammation , immunology , pharmacology , stroke (engine) , brain ischemia , immune system , central nervous system , biology , t cell , microbiology and biotechnology , mechanical engineering , engineering
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. Interpretation Our study suggests that Treg adoptive therapy is a novel and potent cell‐based therapy targeting poststroke inflammatory dysregulation and neurovascular disruption. Ann Neurol 2013;74:458–471