The CD226 and TIGIT Costimulatory Axis in Type 1 Diabetes

1 型糖尿病中的 CD226 和 TIGIT 共刺激轴

• 批准号: 9234529
• 负责人: Todd Michael Brusko
• 金额: $ 33.24万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9234529
• 关键词: Address; Animal Model; Antigen-Presenting Cells; Attenuated; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Binding; Biological Markers; Biological Models; Biological Response Modifier Therapy; CD28 gene; Celiac Disease; Cell Surface Proteins; Cell Therapy; Cells; Chronic Childhood Arthritis; Clinic; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Cytotoxic T-Lymphocyte-Associated Protein 4; Data; Defect; Development; Disease; Disease Progression; Disease susceptibility; Environmental Risk Factor; Epigenetic Process; Eragrostis; Exhibits; Frequencies; Functional disorder; Gene Delivery; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Polymorphism; Genetic Risk; Genomics; Goals; Human; ITIM; Immune; Immune Tolerance; Immune response; Immune system; Immunotherapy; In Vitro; Inbred NOD Mice; Individual; Inflammation; Inflammatory; Insulin; Insulin-Dependent Diabetes Mellitus; Knock-out; Knowledge; Laboratories; Lead; Link; Lupus; Major Histocompatibility Complex; Mediating; Memory; Multiple Sclerosis; Natural History; Pancreas; Pathogenesis; Pathology; Pathway interactions; Peripheral; Phenotype; Population; Regulation; Regulatory T-Lymphocyte; Resistance; Resources; Rheumatoid Arthritis; Risk; Risk Factors; Role; Series; Single Nucleotide Polymorphism; Site; Specificity; Stable Populations; Sum; System; T memory cell; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Thymus Gland; Tissues; Transgenic Model; United States National Institutes of Health; Variant; Wegener' s Granulomatosis; Work; base; cancer therapy; cancer transplantation; cytokine; design; disorder risk; genetic variant; immune activation; immune checkpoint; immunoregulation; in vivo Model; lymph nodes; mouse model; novel; novel strategies; novel therapeutic intervention; novel therapeutics; overexpression; peripheral blood; prevent; programs; public health relevance; receptor; risk variant; small hairpin RNA; targeted treatment; therapeutic evaluation; tool; vector

 DESCRIPTION (provided by applicant): The development of Type 1 Diabetes (T1D) relies on complex interactions between genes imparting disease susceptibility and environmental factors. These interactions influence the cells of the immune system that mediate the autoimmune destruction of insulin-producing pancreatic  cells. Despite the nearly 40 genes that have been identified to confer genetic risk for T1D, the functional impact of these specific gene variants remain poorly characterized. Our studies are designed to address this knowledge gap by providing an understanding for the mechanism by which CD226, a gene linked to risk for multiple autoimmune disorders, impacts immune regulation and may precipitate autoimmune disease in those at risk. CD226 is an immune costimulatory molecule that competes with an inhibitory receptor known as T-cell immunoreceptor with Ig and ITIM domain (TIGIT) for binding to CD155 or CD112 expressed on antigen presenting cells (APC). The CD226:TIGIT regulatory axis is analogous in many ways to the well characterized CD28 and CTLA-4 interaction that has resulted in potent immune modulating therapeutics for the treatment of cancer, transplantation, and autoimmunity. Our preliminary data suggest that CD226 expression on T cells is tightly linked to differentiated memory and effector T cell subsets that are widely thought to drive  cel destruction. In addition, CD226 is expressed on a unique subset of regulatory T cells (Tregs) that exhibit epigenetic instability, reduced suppressive capacity, and produce cytokines. These data have led us to propose the hypothesis that disease-associated variants and inflammatory environmental triggers result in a functional imbalance in the CD226:TIGIT regulatory axis favoring immune activation by CD226 over regulation by TIGIT in T1D. We will test this hypothesis by conducting a series of Aims to i) determine the impact of modulating CD226 and TIGIT expression on T cell activation and regulation, ii) assessing the expression of CD226 and TIGIT throughout the natural history of T1D in the Non-Obese Diabetic mouse model and in humans with T1D, and iii) testing the therapeutic potential of targeting this axis to generate stable regulatory T cells for adoptive immune therapy. These studies will employ novel tools including lentiviral expression systems, directed gene targeting of animals models and human T cells, and the utilization of unique clinical resources to address this question at the site of autoimmune attack in humans with T1D. In sum, data from these Aims are expected to provide information about a key immune checkpoint that impacts autoimmune disease development, and ultimately, lead to novel therapeutic interventions to halt the autoimmune destruction of  cells in T1D.

 描述（由申请人提供）：1型糖尿病（T1 D）的发生依赖于赋予疾病易感性的基因与环境因素之间的复杂相互作用。这些相互作用影响免疫系统的细胞，介导产生胰岛素的胰腺炎细胞的自身免疫性破坏。尽管已经确定了近40个基因赋予T1 D的遗传风险，但这些特定基因变体的功能影响仍然很难表征。我们的研究旨在通过了解CD 226（一种与多种自身免疫性疾病风险相关的基因）影响免疫调节并可能在风险人群中引发自身免疫性疾病的机制来解决这一知识缺口。CD 226是一种免疫共刺激分子，其与称为具有IG和ITIM结构域的T细胞免疫受体（TIGIT）的抑制性受体竞争结合抗原呈递细胞（APC）上表达的CD 155或CD 112。CD 226：TIGIT调节轴在许多方面类似于充分表征的CD 28和CTLA-4相互作用，其已经产生用于治疗癌症、移植和自身免疫的有效免疫调节治疗剂。我们的初步数据表明，CD 226在T细胞上的表达与分化的记忆和效应T细胞亚群密切相关，这些亚群被广泛认为是驱动T细胞破坏的因素。此外，CD 226在调节性T细胞（Tcells）的独特亚群上表达，其表现出表观遗传不稳定性、降低的抑制能力并产生细胞因子。这些数据使我们提出了这样的假设，即疾病相关的变体和炎性环境触发因素导致CD 226：TIGIT调节轴的功能失衡，有利于T1 D中CD 226的免疫激活超过TIGIT的调节。 我们将通过进行一系列目的来测试这一假设，以i）确定调节CD 226和TIGIT表达对T细胞活化和调节的影响，ii）在非肥胖糖尿病小鼠模型和患有T1 D的人中评估整个T1 D自然史中CD 226和TIGIT的表达，和iii）测试靶向该轴以产生用于过继免疫治疗的稳定调节性T细胞的治疗潜力。这些研究将采用新的工具，包括慢病毒表达系统，动物模型和人类T细胞的定向基因靶向，以及利用独特的临床资源来解决T1 D患者自身免疫攻击部位的这一问题。总之，来自这些目标的数据预计将提供有关影响自身免疫性疾病发展的关键免疫检查点的信息，并最终导致新的治疗干预措施，以阻止T1 D中的CD 4+细胞的自身免疫性破坏。