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

• Autor(a) principal: Yshii, L
• Data de Publicação: 2022
• Outros Autores: Pasciuto, E, Bielefeld, P, Mascali, L, Lemaitre, P, Marino, M, Dooley, J, Kouser, L, Verschoren, S, Lagou, V, Kemps, H, Gervois, P, Boer, A, Burton, OT, Wahis, J, Verhaert, J, Tareen, SHK, Roca, CP, Singh, K, Whyte, CE, Kerstens, A, Callaerts-Vegh, Z, Poovathingal, S, Prezzemolo, T, Wierda, K, Dashwood, A, Xie, J, Wonterghem, E, Creemers, E, Aloulou, M, Gsell, W, Abiega, O, Munck, S, Vandenbroucke, RE, Bronckaers, A, Lemmens, R, Strooper, B, Den Bosch, L, Himmelreich, U, Fitzsimons, CP, Holt, MG, Liston, A
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: https://hdl.handle.net/10216/142881

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.