Autism Spectrum Disorders (ASD) are behaviorally defined by deficits in communication, social reciprocity, and repetitive stereotypic behaviors. While genetic and environmental factors are likely contributors to these disorders, little is known about the pathophysiology in ASD. Many in vitro studies, post-mortem brain studies and proteomic studies in plasma and cerebral spinal fluid have described the presence of increased immune activation in ASD, whilst clinical and epidemiological studies suggest that there is an increase in immune mediated conditions such as allergies, asthma and autoimmunity. Activation of these 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 immune control or regulation that can lead to immune activation and inflammation. Our published data and preliminary findings 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 outcomes and more co-morbidities in ASD. In animal models with face and construct validity to ASD decreases in CD4+FoxP3+ regulatory T cells (Tregs) were observed. However, no studies have yet to address the functional cellular mechanisms of Tregs in ASD or their role in animal models of ASD. We will test the innovative hypothesis that a lack of cellular immune regulation by Tregs is a predictive risk factor for ASD diagnosis, and that targeting immune control mechanisms can alleviate behavioral abnormalities. Parallel clinical and preclinical experiments will be performed. The proposed studies will determine the Tregs cellular mechanisms of immune control in cord blood samples from children that later receive a diagnosis of ASD, and compare this to children with typical development (Aim #1). This proposal will directly assess specific cellular mechanisms for which there are novel therapeutic potential. One of these therapeutic approaches, adoptive transfer of Tregs, will be utilized to rescue the behavioral impairments present in a preclinical mouse model that exhibits many features with relevance to ASD (Aim #2). The proposal will directly assess the relationship of immune dysregulation in ASD and behavior abnormalities. If successful, this research will validate the transformative concept that ASD is, for some, a disorder due to defects in immune regulation and control by Tregs, and will validate a novel mechanism for one of the most visible public health concerns of our time.

Public Health Relevance

Autism spectrum disorders (ASD) are pervasive neurodevelopmental disorders with strikingly high prevalence (1:68), the etiology and pathophysiology of which remain largely unknown, although many studies have shown the presence of increased immune activation. We propose that immune activation is due to a defect in immune control/regulation by regulatory T cells (Tregs) that can disrupt neurodevelopment in such a way that impacts behavior and leads to the development of ASD. This hypothesis-driven project will challenge current paradigms and addresses a major gap in ASD research that will provide critical information on the consequences of immune dysfunction in ASD, including translating targeted cellular mechanisms for therapeutic intervention into a functional model.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HD086669-02
Application #
9310349
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Kau, Alice S
Project Start
2016-07-05
Project End
2019-06-30
Budget Start
2017-07-01
Budget End
2019-06-30
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of California Davis
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Rose, Destanie R; Yang, Houa; Serena, Gloria et al. (2018) Differential immune responses and microbiota profiles in children with autism spectrum disorders and co-morbid gastrointestinal symptoms. Brain Behav Immun 70:354-368
Vogel Ciernia, Annie; Careaga, Milo; LaSalle, Janine M et al. (2018) Microglia from offspring of dams with allergic asthma exhibit epigenomic alterations in genes dysregulated in autism. Glia 66:505-521
Lesh, Tyler A; Careaga, Milo; Rose, Destanie R et al. (2018) Cytokine alterations in first-episode schizophrenia and bipolar disorder: relationships to brain structure and symptoms. J Neuroinflammation 15:165
Hughes, Heather K; Ashwood, Paul (2018) Anti-Candida albicans IgG Antibodies in Children With Autism Spectrum Disorders. Front Psychiatry 9:627
Jones, K L; Croen, L A; Yoshida, C K et al. (2017) Autism with intellectual disability is associated with increased levels of maternal cytokines and chemokines during gestation. Mol Psychiatry 22:273-279
Onore, Charity; Yang, Houa; Van de Water, Judy et al. (2017) Dynamic Akt/mTOR Signaling in Children with Autism Spectrum Disorder. Front Pediatr 5:43
Schwartzer, Jared J; Careaga, Milo; Coburn, Morgan A et al. (2017) Behavioral impact of maternal allergic-asthma in two genetically distinct mouse strains. Brain Behav Immun 63:99-107
Schwartzer, Jared J; Onore, Charity E; Rose, Destanie et al. (2017) C57BL/6J bone marrow transplant increases sociability in BTBR T+ Itpr3tf/J mice. Brain Behav Immun 59:55-61
Edmiston, Elizabeth; Ashwood, Paul; Van de Water, Judy (2017) Autoimmunity, Autoantibodies, and Autism Spectrum Disorder. Biol Psychiatry 81:383-390
Rose, Destanie R; Careaga, Milo; Van de Water, Judy et al. (2017) Long-term altered immune responses following fetal priming in a non-human primate model of maternal immune activation. Brain Behav Immun 63:60-70

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