LdIL-2 Treatment in ASD: A Novel Immunotherapeutic Approach Targeting Th/Treg Dysfunction and Neuroinflammation

Abstract

Abstract There was a large part of children with Autism Spectrum Disorder (ASD) were accompanied with immune imbalances. In this study, we attempted to ameliorate the core symptoms of autism by correcting the immune imbalance, especially the T-cell subpopulation imbalance, in BTBR mice with autism through low-dose IL-2 (LdIL-2). We administered LdIL-2 (30,000 IU) subcutaneously to BTBR mice and observed changes in autistic behaviors in the mice before and after treatment. Behavioral tests of the mice included three-chamber test, self-grooming test, sniffing test, marble burying test, and open field test. We also analyzed the changes in peripheral Th/Treg ratios and cytokines, as well as the changes in M1/M2 ratios of microglia in the central nervous system in mice using flow cytometry. Neuroinflammatory proteins in cerebrospinal fluid were detected by proteomic analysis. In addition, we depleted CD25 + Treg cells with PC61 followed by LdIL-2 intervention to observe the role of Treg cells in LdIL-2-treated BTBR mice. We found that the core symptoms of autism in BTBR mice were significantly improved after LdIL-2 treatment. LdIL-2 not only increased the level of Treg cells, reversed the imbalance of Th17/Treg and Tfh/Treg, and improved the immune imbalance. Meanwhile, central nervous system inflammation was reduced in mice. In contrast, the effect of LdIL-2 on behavioral improvement was attenuated after depletion of Treg cells by PC61. This is the first attempt to treat ASD with LdIL-2. LdIL-2 is safe and effective in improving core symptoms and immune imbalance in autism. Improvement in core symptoms was associated with an increase in Treg cell levels in the peripheral blood of BTBR mice after treatment with LdIL-2. LdIL-2 may be a potential therapy for the treatment of core symptoms of autism.