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 (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.

IL-2 secreting T helper cells promote EF B cell maturation via intrinsic regulation of B cell mTOR/AKT/Blimp-1 axis

“…Due to its potent immunomodulatory functions, IL-2 has been also evaluated for clinical purposes in disparate settings, and in a recent study (Yshii et al, 2022) Yshii and colleagues elegantly described a brain-specific IL-2 delivery system capable of protecting mice from pathological neuroinflammation of the central nervous system, a non-lymphoid tissue where also B cells can be recruited and play critical roles (Ahn et al, 2021).…”

Development and characterization of an inducible assay system to measure Zika virus capsid interactions

“…The target gene expression can be detected within 30 min after nontoxic Dox added and maximal expression levels can be higher than expression levels obtained from the CMV promoter 42 . Therefore, the Tet‐on system has been applied to develop a tissue‐specific delivery system on cell therapy and generate controllable transgene expression systems to produce animal models of disease 43–45 . Herein, we first generated inducible cell lines to quantify ZIKV C–C interaction based on the SLCA and Tet‐on system.…”

“…42 Therefore, the Tet-on system has been applied to develop a tissuespecific delivery system on cell therapy and generate controllable transgene expression systems to produce animal models of disease. [43][44][45] Herein, we first generated inducible cell lines to quantify It has been shown recently that α-helix-mediated protein-protein interactions are promising drug targets that can be affected by various types of inhibitors including peptides, foldamers, and proteomimetic-derived ligands. 46 To verify the specificity of the inducible system, we have tested the inhibitory effect of potential peptide inhibitors of ZIKV C-C interaction.…”

“…By using of this system, synthetic peptides Pep.15-24 and Pep. [44][45][46][47][48][49][50][51][52][53][54][55][56][57][58] were identified to inhibit ZIKV C-C interaction. This well-established inducible assay system targeting ZIKV capsid interaction can be applied for future discovery of anti-ZIKV drugs.…”

The Interrelation between Interleukin-2 and Schizophrenia

“…This difference is thought to be related to inflammation. Lidia Yshii and others have found that IL-2 level is a limiting factor for Tregs in the human brain, and brain-specific IL-2 delivery is an effective strategy to suppress neuroinflammation [ 15 ]. The objectives of this review are to explore the possible impact of IL-2 on the prevalence and progression of schizophrenia, as well as the potential of IL-2 to be used as a marker of schizophrenia in order to provide novel insights for the treatment of schizophrenia.…”