Nature Immunology
Author:
Keywords:
Science & Technology, Life Sciences & Biomedicine, Immunology, REG-CELLS, EXPRESSION, MICROGLIA, THERAPY, PACKAGE, SYSTEM, REPAIR, Animals, Astrocytes, Biological Products, Brain, Humans, Interleukin-2, Interleukins, Mice, Neuroinflammatory Diseases, T-Lymphocytes, Regulatory, 12V7519N#54771050, 12V7522N#56382420, 1107 Immunology, 3101 Biochemistry and cell biology, 3204 Immunology
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.