T Cell Tolerance by DEC-205-mediated Islet Antigen Delivery to Dendritic Cells

DEC-205 介导的胰岛抗原递送至树突状细胞的 T 细胞耐受性

基本信息

批准号：
8913153
负责人：
Teresa P DiLorenzo
金额：
$ 36.41万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-20 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8913153
关键词：
Adjuvant Alleles Antibodies Antigen Targeting Antigens Autoantigens Autoimmune Diseases Autoimmunity Beta Cell CD4 Positive T Lymphocytes CD8B1 gene Cell Therapy Cells Characteristics Clinical DEC-205 receptor Defect Dendritic Cells Development Disease Disease remission Fostering Foundations Future Genes HLA A*0201 antigen Health Histocompatibility Antigens Class I Human Immunotherapeutic agent Inbred NOD Mice Infection Insulin Insulin-Dependent Diabetes Mellitus Intervention Islets of Langerhans Knock-out Knockout Mice Knowledge Lead Light Link Mediating Modeling Monitor Morbidity - disease rate Mus Nucleic Acid Regulatory Sequences Pathway interactions Patients Peptides Population Predisposition Prevention Proinsulin Property Reagent Regulatory T-Lymphocyte System T-Cell Development T-Cell Immunologic Specificity T-Lymphocyte Testing Therapeutic Time Transgenic Organisms Translations Work adaptive immunity autoreactive T cell base experience islet meetings mortality mouse model novel pathogen peripheral tolerance response treatment effect

项目摘要

DESCRIPTION (provided by applicant): Type 1 diabetes (T1D) is an autoimmune disease characterized by T cell-mediated destruction of the pancreatic islet beta cells. Our knowledge of at least some of the beta cell antigens targeted by T cells in both the NOD mouse model and T1D patients can now be used practically to develop antigen-based strategies to interfere with pathogenic T cell populations and augment natural tolerance induction pathways. We hypothesize that an effective immunotherapeutic strategy for T1D would be one that eliminates pathogenic CD8+ and CD4+ T cells specific for an important beta cell antigen, while at the same time fostering the expansion of regulatory T cells (Treg) capable of controlling the remaining pathogenic T cells that target a variety of beta cell antigens. We will develop such an approach by taking advantage of our experience in the targeting of antigens to dendritic cells (DC) using antigen-linked antibodies to the DC endocytic receptor DEC- 205. When antigens are delivered in this way in the absence of an adjuvant, DC present them in a tolerogenic manner and cause naive T cells to be deleted, rendered unresponsive, or endowed with regulatory characteristics. Using a reagent that we have recently produced, we propose to deliver the beta cell antigen proinsulin to DC and determine the effect of this treatment on pathogenic CD8+ and CD4+ T cells and on the induction of Treg. These studies will employ an NOD-based mouse model that we have developed (designated NOD.22mnull.HHD.Ins2+/-) that transgenically expresses T1D-associated human HLA-A*0201 and is also heterozygous for an Ins2 knockout allele which leads to diminished thymic insulin expression, hence mimicking the situation in the majority of T1D patients. State-of-the-art mouse models incorporating human cells will also be employed. Finally, our experimental systems will be ideal to determine the pathways by which targeting of antigens to DC can lead to induction of T cell tolerance. Three Specific Aims are proposed: (1) To target proinsulin to DC via DEC-205 and monitor its effects on T cells and the development of T1D in NOD.22mnull.HHD.Ins2+/- mice; (2) To determine whether human islet-reactive T cells can be tolerized in response to DEC-205-mediated delivery of beta cell antigens to DC; (3) To determine the pathways important for the T cell tolerance observed in response to DEC-205-mediated delivery of beta cell antigens to DC. Our proposed studies will have important implications for the development of antigen-specific therapeutics for T1D and will provide information that will help to guide the future development of immunomodulatory therapies for this disease.

描述（由申请人提供）：1型糖尿病（T1D）是一种自身免疫性疾病，其特征是T细胞介导的胰岛胰岛β细胞的破坏。现在，我们对NOD小鼠模型和T1D患者中T细胞靶向的至少某些β细胞抗原的了解实际上可以用于开发基于抗原的策略，以干扰致病性T细胞群体并增强自然耐受性诱导途径。我们假设T1D的有效免疫治疗策略将是消除对重要β细胞抗原特异性的致病性CD8+和CD4+ T细胞，而同一时间则促进了能够控制靶向多种β细胞抗原抗原抗原抗原抗原剂的剩余致病性T细胞的调节性T细胞（TREG）的扩展。 We will develop such an approach by taking advantage of our experience in the targeting of antigens to dendritic cells (DC) using antigen-linked antibodies to the DC endocytic receptor DEC- 205. When antigens are delivered in this way in the absence of an adjuvant, DC present them in a tolerogenic manner and cause naive T cells to be deleted, rendered unresponsive, or endowed with regulatory 特征。使用我们最近生产的试剂，我们提出将β细胞抗原促硫酸蛋白传递到DC，并确定该处理对致病性CD8+和CD4+ T细胞以及Treg诱导的影响。 These studies will employ an NOD-based mouse model that we have developed (designated NOD.22mnull.HHD.Ins2+/-) that transgenically expresses T1D-associated human HLA-A*0201 and is also heterozygous for an Ins2 knockout allele which leads to diminished thymic insulin expression, hence mimicking the situation in the majority of T1D patients.还将采用结合人类细胞的最先进的小鼠模型。最后，我们的实验系统将是确定抗原对直流靶向的途径的理想选择，可以导致T细胞耐受性诱导。提出了三个具体目的：（1）通过DEC-205靶向Droinsulin，并监测其对T细胞的影响以及NOD.22MNULL.HHD.INS2 +/- MICE中T1D的影响；（2）确定是否可以根据DEC-205介导的β细胞抗原向DC递送人类胰岛反应性T细胞；（3）确定对于响应DEC-205介导的β细胞抗原向DC递送的T细胞耐受性很重要的途径。我们提出的研究将对T1D的抗原特异性治疗剂的发展具有重要意义，并将提供信息，以指导该疾病的免疫调节疗法的未来发展。