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

Lidia Yshii, Emanuela Pasciuto, Pascal Bielefeld, Loriana Mascali, Pierre Lemaitre, Marika Marino, James Dooley, Lubna Kouser, Stijn Verschoren, Vasiliki Lagou, et al.
(2022) NATURE IMMUNOLOGY. 23(6). p.878-891
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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 (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. Liston and colleagues design a gene-delivery system to specifically target astrocytes in the central nervous system to express IL-2 and thereby expand/maintain T-reg cells to suppress neuroinflammation.
Keywords
REG-CELLS, EXPRESSION, MICROGLIA, THERAPY, PACKAGE, SYSTEM, REPAIR

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MLA
Yshii, Lidia, et al. “Astrocyte-Targeted Gene Delivery of Interleukin 2 Specifically Increases Brain-Resident Regulatory T Cell Numbers and Protects against Pathological Neuroinflammation.” NATURE IMMUNOLOGY, vol. 23, no. 6, 2022, pp. 878–91, doi:10.1038/s41590-022-01208-z.
APA
Yshii, L., Pasciuto, E., Bielefeld, P., Mascali, L., Lemaitre, P., Marino, M., … Liston, A. (2022). Astrocyte-targeted gene delivery of interleukin 2 specifically increases brain-resident regulatory T cell numbers and protects against pathological neuroinflammation. NATURE IMMUNOLOGY, 23(6), 878–891. https://doi.org/10.1038/s41590-022-01208-z
Chicago author-date
Yshii, Lidia, Emanuela Pasciuto, Pascal Bielefeld, Loriana Mascali, Pierre Lemaitre, Marika Marino, James Dooley, et al. 2022. “Astrocyte-Targeted Gene Delivery of Interleukin 2 Specifically Increases Brain-Resident Regulatory T Cell Numbers and Protects against Pathological Neuroinflammation.” NATURE IMMUNOLOGY 23 (6): 878–91. https://doi.org/10.1038/s41590-022-01208-z.
Chicago author-date (all authors)
Yshii, Lidia, Emanuela Pasciuto, Pascal Bielefeld, Loriana Mascali, Pierre Lemaitre, Marika Marino, James Dooley, Lubna Kouser, Stijn Verschoren, Vasiliki Lagou, Hannelore Kemps, Pascal Gervois, Antina de Boer, Oliver T. Burton, Jerome Wahis, Jens Verhaert, Samar Tareen, Carlos P. Roca, Kailash Singh, Carly E. Whyte, Axelle Kerstens, Zsuzsanna Callaerts-Vegh, Suresh Poovathingal, Teresa Prezzemolo, Keimpe Wierda, Amy Dashwood, Junhua Xie, Elien Van Wonterghem, Eline Creemers, Meryem Aloulou, Willy Gsell, Oihane Abiega, Sebastian Munck, Roosmarijn Vandenbroucke, Annelies Bronckaers, Robin Lemmens, Bart De Strooper, Ludo Van Den Bosch, Uwe Himmelreich, Carlos P. Fitzsimons, Matthew G. Holt, and Adrian Liston. 2022. “Astrocyte-Targeted Gene Delivery of Interleukin 2 Specifically Increases Brain-Resident Regulatory T Cell Numbers and Protects against Pathological Neuroinflammation.” NATURE IMMUNOLOGY 23 (6): 878–891. doi:10.1038/s41590-022-01208-z.
Vancouver
1.
Yshii L, Pasciuto E, Bielefeld P, Mascali L, Lemaitre P, Marino M, 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):878–91.
IEEE
[1]
L. Yshii et al., “Astrocyte-targeted gene delivery of interleukin 2 specifically increases brain-resident regulatory T cell numbers and protects against pathological neuroinflammation,” NATURE IMMUNOLOGY, vol. 23, no. 6, pp. 878–891, 2022.
@article{8760466,
  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 (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. Liston and colleagues design a gene-delivery system to specifically target astrocytes in the central nervous system to express IL-2 and thereby expand/maintain T-reg cells to suppress neuroinflammation.}},
  author       = {{Yshii, Lidia and Pasciuto, Emanuela and Bielefeld, Pascal and Mascali, Loriana and Lemaitre, Pierre and Marino, Marika and Dooley, James and Kouser, Lubna and Verschoren, Stijn and Lagou, Vasiliki and Kemps, Hannelore and Gervois, Pascal and de Boer, Antina and Burton, Oliver T. and Wahis, Jerome and Verhaert, Jens and Tareen, Samar and Roca, Carlos P. and Singh, Kailash and Whyte, Carly E. and Kerstens, Axelle and Callaerts-Vegh, Zsuzsanna and Poovathingal, Suresh and Prezzemolo, Teresa and Wierda, Keimpe and Dashwood, Amy and Xie, Junhua and Van Wonterghem, Elien and Creemers, Eline and Aloulou, Meryem and Gsell, Willy and Abiega, Oihane and Munck, Sebastian and Vandenbroucke, Roosmarijn and Bronckaers, Annelies and Lemmens, Robin and De Strooper, Bart and Van Den Bosch, Ludo and Himmelreich, Uwe and Fitzsimons, Carlos P. and Holt, Matthew G. and Liston, Adrian}},
  issn         = {{1529-2908}},
  journal      = {{NATURE IMMUNOLOGY}},
  keywords     = {{REG-CELLS,EXPRESSION,MICROGLIA,THERAPY,PACKAGE,SYSTEM,REPAIR}},
  language     = {{eng}},
  number       = {{6}},
  pages        = {{878--891}},
  title        = {{Astrocyte-targeted gene delivery of interleukin 2 specifically increases brain-resident regulatory T cell numbers and protects against pathological neuroinflammation}},
  url          = {{http://doi.org/10.1038/s41590-022-01208-z}},
  volume       = {{23}},
  year         = {{2022}},
}
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