Nat Neurosci | Scientists Discover Therapeutical Potential of Adoptive Cell Transfer in Rescuing MIA-induced Behavioral Abnormalities
Update time：2021-04-18
Autism spectrum disorder (ASD, also known as autism) is a group of developmental diseases of the central nervous system, with complex pathogenic mechanisms and highly heterogeneous etiology. So far, there is no effective treatment drug in clinical settings.
Genetic studies have found hundreds of genetic abnormalities in patients with autism, resulting in a lack of universal drug targets to support conventional models of drug development. Meantime, there is a "immune abnormality" phenomenon in ASD patients. Epidemiologic evidence in humans and experimental animal studies have implicated a possible role for prenatal maternal infections and resultant immune activation (MIA), in the pathogenesis of neuropsychiatric disorders such as ASD in offspring.
In a study published in Nature Neuroscience (IF=24.884), the research group of ZHOU Zikai from the Zhongshan Institute for Drug Discovery , together with the collaborators, reported a novel animal model of parasite-mimicking maternal immune activation (MIA), revealed immuno-neurological mechanisms underlying MIA-induced behavioral abnormalities, and demonstrated therapeutic efficacy of adoptive transfer of regulatory T cells (Tregs) in rescuing phenotypes associated with immune alterations.
In this study, the scientists used the soluble tachyzoite antigen (STAg) from T. gondii to induce MIA in mice. They found that this approach induced profound and chronic dysregulation of immune profiling in the brain and peripheral circulation in adult offspring, and reproduced pathogen-specific adaptive cellular immune responses that highly resemble the CD4+ T-cell profile observed in autistic children. In the brain, STAg-MIA induced IL-6 upregulation in astrocytes, and altered neuronal connectivity, as revealed by diffusion tensor imaging (DTI). Moreover, the MIA offspring mice manifested autism-relevant behaviors, namely abnormal social interactions, communication deficits and repetitive stereotyped behaviors.
Based on dysregulated CD4+ T-cell profile, the scientists employed adoptive cell transfer (ACT) of activated Tregs cells, and rescued MIA-induced immunological and behavioral abnormalities in this animal model.
This study established a new preclinical parasite-mimicking MIA model, presented mechanistic insights into pathogenesis of MIA-induced phenotypes, and demonstrated potential feasibility of managing neurodevelopmental conditions by immune cell therapy in peripheral circulation.
Graphical abstract: A proposed model showing STAg-MIA which induces immuno-neurological dysfunctions in adult offspring that can be reversed by adoptive transfer of Treg cells. (Image by XU Zhipeng)
DOI：https://doi.org/10.1038/s41593-021-00837-1
Link to article：https://www.nature.com/articles/s41593-021-00837-1
Contributing Department: Research Group of ZHOU Zikai