LdIL-2 treatment in ASD: a novel immunotherapeutic approach targeting Th/Treg dysfunction and neuroinflammation
Meng Li, Xiuying Kui, Shujun Yang, Zuqing Nie, Huiling Chen, Penghao Yao, Xinyi Xu, Chen‐Yang Shen, Zhiwei Li, Huijia Zhao, Jie Wen, Xinwei Huang, Jingrui Yang, Jinyuan Yan, Pengfei Wang, Bin Li, Xia Cao
Abstract
A significant proportion of children with Autism Spectrum Disorder (ASD) present with immune imbalances. In this study, we sought to alleviate the core symptoms of autism by addressing immune dysregulation, especially T-cell subpopulation imbalances, in BTBR mice through low-dose IL-2 (LdIL-2) treatment. LdIL-2 (30,000 IU) was administered subcutaneously, and changes in autistic behaviors were observed before and after treatment. Behavioral assessments included the three-chamber test, self-grooming test, sniffing test, marble burying test, open field test and Y-maze test. We also examined alterations in peripheral Th/Treg ratios, cytokine levels, and M1/M2 microglia ratios in the central nervous system via flow cytometry. Neuroinflammatory proteins in cerebrospinal fluid were assessed using proteomic analysis. Furthermore, CD25 + Treg cells were depleted using PC61, followed by LdIL-2 intervention, to determine the role of Treg cells in LdIL-2-treated BTBR mice. Our results demonstrated that LdIL-2 significantly ameliorated core symptoms of autism in BTBR mice. LdIL-2 treatment increased Treg cell levels, restored Th17/Treg and Tfh/Treg balance, and corrected immune dysregulation. Central nervous system inflammation was reduced in mice. However, the behavioral improvements were diminished when Treg cells were depleted by PC61. This study represents the first attempt to treat ASD using LdIL-2. The treatment proved safe and effective in improving both core symptoms and immune imbalances in autism. Symptom improvement was linked to increased Treg cell levels in peripheral blood. LdIL-2 shows potential as a novel therapy for addressing core symptoms of autism.