Immune regulation and neurodevelopmental disorders

项目摘要/摘要：自闭症谱系障碍(ASD)的行为定义为 沟通、社会互惠和重复的刻板行为。虽然遗传和环境 这些因素可能是这些疾病的贡献者，对ASD的病理生理学知之甚少。许多人在体外 研究、死后脑研究以及血浆和脑脊液中的蛋白质组学研究描述了 ASD中存在免疫激活增加，而临床和流行病学研究表明 过敏、哮喘和自身免疫等免疫介导性疾病的发生率增加。激活 这些免疫反应在ASD患者行为损害加重的个体中更为突出。 我们假设，这些不同发现的一个共同的潜在机制是缺乏免疫力 可导致免疫激活和炎症的控制或调节。我们公布的数据和初步数据 研究结果提示缺乏免疫调节细胞因子的产生，如转化生长因子β1 (转化生长因子β1)和白介素10。这些因素的减少与较差的行为结果相关。 在ASD中有更多的并存。在有面孔和结构的动物模型中，ASD的有效性降低 观察CD4+FoxP3+调节性T细胞(Tregs)的表达。然而，还没有研究解决功能 ASD中Tregs的细胞机制及其在ASD动物模型中的作用。我们将测试创新的 假设缺乏Tregs的细胞免疫调节是ASD诊断的预测风险因素，以及 靶向免疫控制机制可以减轻行为异常。并行临床和 将进行临床前实验。拟议的研究将确定Tregs的细胞机制。 后来被诊断为ASD的儿童脐带血样本中的免疫控制，并将其与 具有典型发育的儿童(目标1)。这项提案将直接评估特定的细胞机制 有新的治疗潜力。其中一种治疗方法，即Tregs收养转移，将 被用来挽救临床前小鼠模型中出现的行为障碍 与ASD相关的特征(目标2)。该提案将直接评估免疫的关系 自闭症的调节失调和行为异常。如果成功，这项研究将验证 变革性的概念，对一些人来说，ASD是一种由于免疫调节和控制缺陷而引起的疾病 Tregs，并将验证一种新的机制，以解决我们时代最明显的公共卫生问题之一。

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.