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

Published version
Peer-reviewed

Change log

Authors

Yshii, Lidia 
Bielefeld, Pascal 
Mascali, Loriana 
Lemaitre, Pierre 

Abstract

The 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.

Description

Keywords

Article, /631/250/371, /631/250/251, /631/250/127/1213, /631/250/1619/554/1898/1271, article

Journal Title

Nat Immunol

Conference Name

Journal ISSN

1529-2908
1529-2916

Volume Title

23

Publisher

Springer Science and Business Media LLC
Sponsorship
EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council) (TreatBrainDamage, TissueTregs, AstroFunc)
RCUK | Biotechnology and Biological Sciences Research Council (BBSRC) (BBS/E/B/000C0428, BBS/E/B/000C0427)
Internationale Stichting Alzheimer Onderzoek (ISAO) (20190032)
Fondation Thierry Latran (Thierry Latran Foundation) (SOD-VIP)