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Article Dans Une Revue Nature Immunology Année : 2022

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

James Dooley
Hannelore Kemps
Pascal Gervois
Oliver Burton
Kailash Singh
Carly Whyte
Amy Dashwood

Résumé

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 (T reg ) 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 T reg 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.

Dates et versions

hal-04009626 , version 1 (01-03-2023)

Identifiants

Citer

Lidia Yshii, Emanuela Pasciuto, Pascal Bielefeld, Loriana Mascali, Pierre Lemaitre, et al.. Astrocyte-targeted gene delivery of interleukin 2 specifically increases brain-resident regulatory T cell numbers and protects against pathological neuroinflammation. Nature Immunology, 2022, 23 (6), pp.878-891. ⟨10.1038/s41590-022-01208-z⟩. ⟨hal-04009626⟩
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