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

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 cells (Tregs) resident in the brain presents one such potential therapeutic target. Here we identified brain IL2 levels as a limiting factor for brain-resident Tregs. 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 IL2 delivery were protected from traumatic brain injury, stroke and multiple sclerosis models, without impacting the peripheral immune system. These results validate brain-specific IL2 gene-delivery as effective protection against neuroinflammation, and provide a versatile platform for delivery of diverse biologics to neuroinflammatory patients.

Molecular and cognitive signatures of ageing partially restored through synthetic delivery of IL2 to the brain

“…Surprisingly, the local provision of IL2 in the brain was su cient to substantially revert almost all of these age-induced pathway changes across microglia, oligodendrocytes and astrocytes. This was despite relatively few immune pathways being identi ed as altered, apart from the upregulation of MHCII, previously linked to PHP.GFAP-IL2 treatment [43], and alterations in the TLR and IL17 signaling pathways in microglia. Whether this effect is mediated via direct reprogramming, such as Treg cytokine-mediated effects, or indirect effects of microenvironmental cleansing, remains to be seen.…”

“…When considering the e cacy of PHP.GFAP-IL2 in mitigating aging effects, the parsimonious explanation would be a primary effect via the local expansion of Tregs. When used in the context of traumatic brain injury, the bene cial effects of PHP.GFAP-IL2 were only observed in the presence of an adaptive immune system, suggesting that the levels of IL2 achieved (~ 2pg/ml) are too low to trigger the activation of the lower a nity receptor expressed in non-Treg lineages [43]. While it would be attractive to speculate on the role of individual downstream mediators, the complexity and interdependencies of aging make a multifactorial function more likely, integrating prorepair, anti-in ammatory and glial reprogramming functions.…”

“…This approach results in the restricted production of IL2 in the brain, and an accompanying expansion of brain-resident Tregs [43]. PHP.GFAP-IL2 treatment is protective against neuroin ammation in the context of traumatic brain injury, stroke and experimental autoimmune encephalitis [43]. In order to test the in uence of brain-speci c IL2 delivery on ageing, we treated young mice, at 2 months of age, and old mice, at 22 months of age, with PHP.GFAP-IL2 or the control PHP.GFAP-GFP vector.…”

“…One way to achieve brain-speci c expression of IL2 is through the genedelivery vector PHP.GFAP-IL2. This approach results in the restricted production of IL2 in the brain, and an accompanying expansion of brain-resident Tregs [43]. PHP.GFAP-IL2 treatment is protective against neuroin ammation in the context of traumatic brain injury, stroke and experimental autoimmune encephalitis [43].…”

“…Despite the growing recognition of a protective role of IL2 and Tregs in neuroin ammatory and neurodegenerative processes, the potential of these cells to protect the ageing brain remain unknown. Here, we used the synthetic delivery of brain-speci c IL2, which was recently demonstrated to protect against neuroin ammatory injury and disease [43], to test the hypothesis that neurological ageing can be restrained by modulation of the immunological compartment of the brain. Using young and aged mice we characterized the molecular signature of aging in the brain stroma, and found IL2 capable of restraining a core component of the molecular aging process across glial types.…”