The CD226 and TIGIT Costimulatory Axis in Type 1 Diabetes

1 型糖尿病中的 CD226 和 TIGIT 共刺激轴

基本信息

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
项目类别：
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&apos 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

项目摘要

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（申请人证明）：1型糖尿病（T1D）的发展依赖于赋予胰岛抗性性和环境因素的基因之间的复杂相互作用。我们的研究旨在增加与多种自身免疫性疾病的风险相关的基因，从而增加了这种知识差距，从而增加了这种知识差距风险CD226是一种免疫刺激分子，与IG和ITIM域（Tigit）（Tigit）的抑制受体竞争，以与CD155或CD112结合在抗原上表达的CD155或CD112。在许多方面类似于良好的表征2 8和CTLA-4相互作用，这导致了有效的免疫调节癌，移植和自身免疫性的治疗疗法，这表明我们的初步数据表明CD226与差异很大程度上链接到差异范围。此外，CD226在一个独特的监管TCELLS（TREGSS（Tregss））的子集中表达，表现出表观遗传不稳定性，并产生细胞因子。这些数据导致了与疾病相关的变体和炎症的损害CD226：CD226对Tigit在T1D中的调节而进行的Tigit调节免疫激活。 Thout T1D在非奥特糖尿病穆斯尔和具有T1D的人类中的自然历史，以及iii）测试靶向靶向TOTORY T细胞的治疗疗法，用于采用免疫治疗。动物和人类的T细胞，以及独特的临床来解决此问题的位置是具有T1D的人类的自身免疫性ACK。最终，导致新的治疗干预措施停止T1D细胞的自身免疫性破坏。