Project Summary/Abstract: Autism Spectrum Disorders (ASD) are behaviorally defined by deficits incommunication, social reciprocity, and repetitive stereotypic behaviors. While genetic and environmentalfactors are likely contributors to these disorders, little is known about the pathophysiology in ASD. Many in vitrostudies, post-mortem brain studies and proteomic studies in plasma and cerebral spinal fluid have describedthe presence of increased immune activation in ASD, whilst clinical and epidemiological studies suggest thatthere is an increase in immune mediated conditions such as allergies, asthma and autoimmunity. Activation ofthese immune responses is more prominent in individuals with exacerbated behavioral impairments in ASD.We hypothesize that an underlying mechanism common to this diverse array of findings is the lack of immunecontrol or regulation that can lead to immune activation and inflammation. Our published data and preliminaryfindings suggest a lack of production of immune regulatory cytokines such as transforming growth factor beta 1(TGF?1) and interleukin (IL)-10. Decreases in these factors were associated with worse behavioral outcomesand more co-morbidities in ASD. In animal models with face and construct validity to ASD decreases inCD4+FoxP3+ regulatory T cells (Tregs) were observed. However, no studies have yet to address the functionalcellular mechanisms of Tregs in ASD or their role in animal models of ASD. We will test the innovativehypothesis that a lack of cellular immune regulation by Tregs is a predictive risk factor for ASD diagnosis, andthat targeting immune control mechanisms can alleviate behavioral abnormalities. Parallel clinical andpreclinical experiments will be performed. The proposed studies will determine the Tregs cellular mechanisms ofimmune control in cord blood samples from children that later receive a diagnosis of ASD, and compare this tochildren with typical development (Aim #1). This proposal will directly assess specific cellular mechanisms forwhich there are novel therapeutic potential. One of these therapeutic approaches, adoptive transfer of Tregs, willbe utilized to rescue the behavioral impairments present in a preclinical mouse model that exhibits manyfeatures with relevance to ASD (Aim #2). The proposal will directly assess the relationship of immunedysregulation in ASD and behavior abnormalities. If successful, this research will validate thetransformative concept that ASD is, for some, a disorder due to defects in immune regulation and control byTregs, and will validate a novel mechanism for one of the most visible public health concerns of our time.
|Effective start/end date||7/5/16 → 6/30/18|
- National Institutes of Health: $235,500.00