Immune regulation and neurodevelopmental disorders

免疫调节和神经发育障碍

• 批准号: 9182583
• 负责人: Paul Ashwood
• 金额: $ 23.55万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-05 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9182583
• 关键词: 3 year old; Address; Adoptive Cell Transfers; Adoptive Transfer; Affect; Animal Model; Asthma; Autoimmune Process; Autoimmunity; Behavior; Behavioral; Behavioral Symptoms; Blood specimen; Bone Marrow Transplantation; Brain; Cell surface; Cells; Cerebrospinal Fluid; Child; Clinical; Clinical Research; Coculture Techniques; Communication; Comorbidity; Cytotoxic T-Lymphocyte-Associated Protein 4; Data; Defect; Development; Diagnosis; Disease; Documentation; Environmental Risk Factor; Epidemiologic Studies; Etiology; Exhibits; Face; Frequencies; Functional disorder; Genetic; High Prevalence; Hypersensitivity; Immune; Immune System Diseases; Immune System and Related Disorders; Immune Targeting; Immune response; Immune system; Immunologics; Immunosuppressive Agents; Impairment; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Interleukin-10; Interleukins; Investigation; Knowledge; Laboratories; Lead; Life; Mediating; Mediator of activation protein; Modeling; Neurodevelopmental Disorder; Outcome; Pathology; Pathway interactions; Perinatal; Phenotype; Plasma; Population; Pre-Clinical Model; Production; Proteomics; Public Health; Publishing; Regulation; Regulatory T-Lymphocyte; Reporting; Research; Risk; Risk Factors; Role; TGFB1 gene; Testing; Therapeutic; Therapeutic Intervention; Time; Transforming Growth Factor beta; Transforming Growth Factors; Translating; Umbilical Cord Blood; United States; abstracting; autism spectrum disorder; behavioral impairment; behavioral outcome; cell type; cellular targeting; cytokine; drug discovery; immune activation; immune function; improved; innovation; latency-associated protein; mouse model; neurodevelopment; novel; novel therapeutics; peripheral tolerance; pre-clinical; prevent; reconstitution; research study; response; social reciprocity; species typical behavior; stem

Project Summary/Abstract: 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 (TGFβ1) 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.

项目摘要/摘要：自闭症谱系障碍（ASD）在行为上被定义为 沟通，社会互惠和重复的刻板行为。虽然遗传和环境 虽然这些因素可能是这些疾病的贡献者，但对ASD的病理生理学知之甚少。许多体外 研究、死后脑研究和血浆和脑脊液中的蛋白质组学研究已经描述了 ASD中免疫激活增加的存在，而临床和流行病学研究表明， 免疫介导的病症如过敏、哮喘和自身免疫增加。激活 这些免疫应答在ASD中具有加重的行为损伤的个体中更加突出。 我们推测，这些不同发现的一个共同的潜在机制是缺乏免疫调节。 控制或调节，可导致免疫激活和炎症。我们公布的数据和初步 研究结果表明，缺乏免疫调节细胞因子的产生，如转化生长因子β 1 (TGFβ1）和白细胞介素（IL）-10。这些因素的减少与更差的行为结果有关 自闭症的并发症也更多在ASD的面部和结构效度的动物模型中， 观察到CD 4 + FoxP 3+调节性T细胞（T细胞）。然而，还没有研究涉及功能性 ASD中的细胞机制或其在ASD动物模型中的作用。我们将测试创新 缺乏TGFAP的细胞免疫调节是ASD诊断的预测风险因素的假设，以及 针对免疫控制机制可以减轻行为异常。平行临床和 将进行临床前实验。拟议的研究将确定T细胞的机制， 在后来接受ASD诊断的儿童的脐带血样本中进行免疫控制，并将其与 具有典型发展的儿童（目标1）。这项提案将直接评估特定的细胞机制， 具有新的治疗潜力。这些治疗方法之一，过继性转移Tlymphocyte，将 用于挽救临床前小鼠模型中存在的行为障碍， 与ASD相关的功能（目标#2）。该建议将直接评估免疫的关系 ASD失调和行为异常。如果成功，这项研究将验证 对于一些人来说，ASD是一种由于免疫调节和控制缺陷引起的疾病， 它将为我们这个时代最明显的公共卫生问题之一验证一种新的机制。