Astrocyte-targeted gene delivery of interleukin 2 specifically increases brain-resident regulatory T cell numbers and protects against pathological neuroinflammation.

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cam.issuedOnline2022-05-26
dc.contributor.authorYshii, Lidia
dc.contributor.authorPasciuto, Emanuela
dc.contributor.authorBielefeld, Pascal
dc.contributor.authorMascali, Loriana
dc.contributor.authorLemaitre, Pierre
dc.contributor.authorMarino, Marika
dc.contributor.authorDooley, James
dc.contributor.authorKouser, Lubna
dc.contributor.authorVerschoren, Stijn
dc.contributor.authorLagou, Vasiliki
dc.contributor.authorKemps, Hannelore
dc.contributor.authorGervois, Pascal
dc.contributor.authorde Boer, Antina
dc.contributor.authorBurton, Oliver T
dc.contributor.authorWahis, Jérôme
dc.contributor.authorVerhaert, Jens
dc.contributor.authorTareen, Samar HK
dc.contributor.authorRoca, Carlos P
dc.contributor.authorSingh, Kailash
dc.contributor.authorWhyte, Carly E
dc.contributor.authorKerstens, Axelle
dc.contributor.authorCallaerts-Vegh, Zsuzsanna
dc.contributor.authorPoovathingal, Suresh
dc.contributor.authorPrezzemolo, Teresa
dc.contributor.authorWierda, Keimpe
dc.contributor.authorDashwood, Amy
dc.contributor.authorXie, Junhua
dc.contributor.authorVan Wonterghem, Elien
dc.contributor.authorCreemers, Eline
dc.contributor.authorAloulou, Meryem
dc.contributor.authorGsell, Willy
dc.contributor.authorAbiega, Oihane
dc.contributor.authorMunck, Sebastian
dc.contributor.authorVandenbroucke, Roosmarijn E
dc.contributor.authorBronckaers, Annelies
dc.contributor.authorLemmens, Robin
dc.contributor.authorDe Strooper, Bart
dc.contributor.authorVan Den Bosch, Ludo
dc.contributor.authorHimmelreich, Uwe
dc.contributor.authorFitzsimons, Carlos P
dc.contributor.authorHolt, Matthew G
dc.contributor.authorListon, Adrian
dc.contributor.orcidPasciuto, Emanuela [0000-0002-5391-9585]
dc.contributor.orcidMarino, Marika [0000-0001-6773-6176]
dc.contributor.orcidDooley, James [0000-0003-3154-4708]
dc.contributor.orcidVerschoren, Stijn [0000-0001-6733-3481]
dc.contributor.orcidKemps, Hannelore [0000-0001-9248-1697]
dc.contributor.orcidGervois, Pascal [0000-0002-8320-1320]
dc.contributor.orcidBurton, Oliver T [0000-0003-3884-7373]
dc.contributor.orcidSingh, Kailash [0000-0002-6771-7757]
dc.contributor.orcidWhyte, Carly E [0000-0001-6556-6855]
dc.contributor.orcidCallaerts-Vegh, Zsuzsanna [0000-0001-9091-2078]
dc.contributor.orcidDashwood, Amy [0000-0002-4340-377X]
dc.contributor.orcidGsell, Willy [0000-0001-7334-6107]
dc.contributor.orcidVandenbroucke, Roosmarijn E [0000-0002-8327-620X]
dc.contributor.orcidListon, Adrian [0000-0002-6272-4085]
dc.date.accessioned2022-06-29T19:47:31Z
dc.date.available2022-06-29T19:47:31Z
dc.date.issued2022-06
dc.date.updated2022-06-29T19:47:31Z
dc.description.abstractThe ability of immune-modulating biologics to prevent and reverse pathology has transformed recent clinical practice. Full utility in the neuroinflammation space, however, requires identification of both effective targets for local immune modulation and a delivery system capable of crossing the blood-brain barrier. The recent identification and characterization of a small population of regulatory T (Treg) cells resident in the brain presents one such potential therapeutic target. Here, we identified brain interleukin 2 (IL-2) levels as a limiting factor for brain-resident Treg cells. We developed a gene-delivery approach for astrocytes, with a small-molecule on-switch to allow temporal control, and enhanced production in reactive astrocytes to spatially direct delivery to inflammatory sites. Mice with brain-specific IL-2 delivery were protected in traumatic brain injury, stroke and multiple sclerosis models, without impacting the peripheral immune system. These results validate brain-specific IL-2 gene delivery as effective protection against neuroinflammation, and provide a versatile platform for delivery of diverse biologics to neuroinflammatory patients.
dc.identifier.doi10.17863/CAM.85955
dc.identifier.eissn1529-2916
dc.identifier.issn1529-2908
dc.identifier.other35618831
dc.identifier.otherPMC9174055
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/338542
dc.languageeng
dc.publisherSpringer Science and Business Media LLC
dc.publisher.urlhttp://dx.doi.org/10.1038/s41590-022-01208-z
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourceessn: 1529-2916
dc.sourcenlmid: 100941354
dc.subjectAnimals
dc.subjectAstrocytes
dc.subjectBiological Products
dc.subjectBrain
dc.subjectHumans
dc.subjectInterleukin-2
dc.subjectInterleukins
dc.subjectMice
dc.subjectNeuroinflammatory Diseases
dc.subjectT-Lymphocytes, Regulatory
dc.titleAstrocyte-targeted gene delivery of interleukin 2 specifically increases brain-resident regulatory T cell numbers and protects against pathological neuroinflammation.
dc.typeArticle
dcterms.dateAccepted2022-04-11
prism.endingPage891
prism.issueIdentifier6
prism.publicationNameNat Immunol
prism.startingPage878
prism.volume23
pubs.funder-project-idEuropean Research Council (TreatBrainDamage, TissueTregs, AstroFunc)
pubs.funder-project-idBiotechnology and Biological Sciences Research Council (BBS/E/B/000C0427, BBS/E/B/000C0428)
pubs.funder-project-idFondation Thierry Latran (Thierry Latran Foundation) (SOD-VIP)
pubs.funder-project-idInternationale Stichting Alzheimer Onderzoek (ISAO) (20190032)
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1038/s41590-022-01208-z
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