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 (T1D) 的发展依赖于赋予疾病易感性的基因与环境因素之间复杂的相互作用。这些相互作用会影响免疫系统的细胞，从而介导产生胰岛素的胰腺  细胞的自身免疫破坏。尽管已确定近 40 个基因可赋予 T1D 遗传风险，但这些特定基因变异的功能影响仍知之甚少。我们的研究旨在通过了解 CD226（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促使高危人群罹患自身免疫性疾病的机制来解决这一知识差距。 CD226 是一种免疫共刺激分子，与具有 Ig 和 ITIM 结构域的 T 细胞免疫受体 (TIGIT) 竞争，与抗原呈递细胞 (APC) 上表达的 CD155 或 CD112 结合。 CD226:TIGIT 调节轴在许多方面与已充分表征的 CD28 和 CTLA-4 相互作用相似，后者导致了用于治疗癌症、移植和自身免疫的有效免疫调节疗法。我们的初步数据表明，T 细胞上的 CD226 表达与分化的记忆和效应 T 细胞亚群密切相关，人们普遍认为这些细胞亚群会驱动  细胞破坏。此外，CD226 在调节性 T 细胞 (Treg) 的独特子集上表达，这些细胞表现出表观遗传不稳定、抑制能力降低并产生细胞因子。这些数据使我们提出这样的假设：在 T1D 中，疾病相关变异和炎症环境触发因素导致 CD226:TIGIT 调节轴功能失衡，有利于 CD226 的免疫激活而不是 TIGIT 的调节。 我们将通过进行一系列的目标来检验这一假设：i) 确定调节 CD226 和 TIGIT 表达对 T 细胞激活和调节的影响，ii) 在非肥胖糖尿病小鼠模型和患有 T1D 的人类 T1D 自然史中评估 CD226 和 TIGIT 的表达，以及 iii) 测试靶向该轴以生成稳定的调节性 T 细胞用于收养的治疗潜力 免疫治疗。这些研究将采用新工具，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人类 T1D 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 T1D 中  细胞的自身免疫破坏。