Back to Search
Start Over
Astrocyte-targeted gene delivery of interleukin 2 specifically increases brain-resident regulatory T cell numbers and protects against pathological neuroinflammation
- Source :
- Nature Immunology, Nature Immunology, 2022, 23 (6), pp.878-891. ⟨10.1038/s41590-022-01208-z⟩, Nature Immunology, 23(6), 878-891. Nature Publishing Group, NATURE IMMUNOLOGY
- Publication Year :
- 2022
- Publisher :
- NATURE PORTFOLIO, 2022.
-
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. The work was supported by the VIB, an ERC Consolidator Grant TissueTreg (to A.L.), an ERC Proof of Concept Grant TreatBrainDamage (to A.L.), an ERC Starting Grant AstroFunc (to M.G.H.), an ERC Proof of Concept Grant AD-VIP (to M.G.H.), FWO Research Grant 1513616N (to M.G.H.), Thierry Latran Foundation Grant SOD-VIP (to M.G.H.), an ERNAET Chair (H2020-WIDESPREAD-2018-2020-6; NCBio: 951923; to M.G.H.), FWO Research Grants 1503420N (to E.P.) and 1513020N (to J.W.), an SAO-FRA pilot grant (20190032, to E.P.), and the Biotechnology and Biological Sciences Research Council through Institute Strategic Program Grant funding BBS/E/B/000C0427 and BBS/E/B/000C0428, and the Biotechnology and Biological Sciences Research Council Core Capability Grant to the Babraham Institute. E.P., V.L., M.M., P.G., J.W. and A.d.B. were supported by fellowships from the FWO. R.L. is a senior clinical investigator of FWO Flanders. P.B., O.A. and C.P.F. were supported by an ERA-NET-NEURON grant EJTC 2016 to C.P.F. and by the Netherlands Organization for Scientific research (NWO). The authors acknowledge the important contributions of J. Haughton (VIB) for mouse husbandry, M. Rincon (VIB) for advice on AAV design and production, K. Vennekens for technical support, P. -A. Penttila and the KUL FACS Core, J. Wouters and the KUL Molecular Small Animal Imaging Center (MoSAIC), S. Walker and the Babraham Institute Imaging Core, the VIB Bio-Imaging Core, the VIB Single Cell Sequencing Core, and R. Breedijk, M. Hink and the Leeuwenhoek Center for Advanced Microscopy at the University of Amsterdam.
- Subjects :
- EXPRESSION
Immunology
Neuroimmunology
631/250/127/1213
THERAPY
T-Lymphocytes, Regulatory
MICROGLIA
Mice
Medicine and Health Sciences
Immunology and Allergy
Animals
Humans
Interleukin-2 / genetics
REPAIR
Biological Products
[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology
Interleukins
article
Biology and Life Sciences
631/250/371
Brain
631/250/251
REG-CELLS
Regulatory T cells
Astrocytes
631/250/1619/554/1898/1271
Neuroinflammatory Diseases
Interleukin-2
Immunotherapy
SYSTEM
[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
PACKAGE
Subjects
Details
- Language :
- English
- ISSN :
- 15292908 and 15292916
- Database :
- OpenAIRE
- Journal :
- Nature Immunology, Nature Immunology, 2022, 23 (6), pp.878-891. ⟨10.1038/s41590-022-01208-z⟩, Nature Immunology, 23(6), 878-891. Nature Publishing Group, NATURE IMMUNOLOGY
- Accession number :
- edsair.doi.dedup.....46ab80cea5714e906bd81ffe84b531cc