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

• 批准号: 8069754
• 负责人: Teresa P DiLorenzo
• 金额: $ 28.22万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8069754
• 关键词: Antibodies; Antigen Targeting; Antigens; Arts; Autoantigens; Autoimmune Diseases; Autoimmunity; Beta Cell; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Therapy; Cells; Characteristics; DEC-205 receptor; Defect; Dendritic Cell Pathway; Dendritic Cells; Development; Epitopes; Foundations; Future; Generations; HLA A*0201 antigen; HLA-A gene; Health; Human; Immune response; Inbred NOD Mice; Individual; Infection; Insulin; Insulin-Dependent Diabetes Mellitus; Investigation; Islets of Langerhans; Knowledge; Lead; Light; Link; Maps; Mediating; Monitor; Morbidity - disease rate; Mus; Non obese; Paper; Pathway interactions; Patients; Peptides; Population; Prevention; Proteins; Reagent; Study models; System; T-Lymphocyte; T-Lymphocyte Epitopes; Technology; Testing; Transgenic Organisms; Work; autoreactive T cell; base; clinically relevant; diabetic; disorder prevention; efficacy testing; glucose-6-phosphatase; human disease; islet; mortality; mouse model; novel; pathogen; peripheral tolerance; preproinsulin; response

Type 1 diabetes (T1D) is an autoimmune disease characterized by T cell-mediated destruction of the pancreatic islet β cells. NOD mice constitute an extensively studied model for T1D sharing many characteristics with the human disease. Our knowledge of at least some of the β cell antigens targeted by T cells in both NOD mice and T1D patients can now be used practically to develop antigen-based strategies to interfere with pathogenic autoreactive T cell populations and to better understand and augment natural tolerance induction pathways. Dendritic cells (DCs) are critical for the initiation of adaptive immune responses to pathogens. However, in the steady-state, DCs present antigens to T cells in a tolerogenic manner and are important for the establishment of peripheral tolerance. While this was known to be the case in mice that are not prone to the development of autoimmunity, we recently evaluated this concept in the setting of a spontaneous autoimmune disease. We delivered a mimotope peptide, recognized by the diabetogenic NODderived CD8+ T cell clone AI4, to DCs in NOD mice using a peptide-linked antibody to the DC endocytic receptor DEC-205. Proliferation of transferred antigen-specific T cells was initially observed, but this was followed by deletion. Thus, selective antigen targeting of DCs leads to deletion of transferred autoreactive CD8+ T cells even in the context of ongoing autoimmunity in NOD mice with known tolerance defects. While promising, a substantial quantity of additional investigation must be performed before the application of such technology to patients with T1D. Our objectives are to move this strategy in a stepwise fashion to humanized mouse models of increasing relevance to patients with T1D. Four Specific Aims are proposed: Aim 1a. To determine whether targeting of CD8+ T cell epitopes of β cell antigens to steadystate DCs via DEC-205 can result in deletion of endogenous antigen-specific T cells in HLA-A*0201- transgenic NOD mice. Aim 1b. To test the efficacy of antigen targeting to DCs for the prevention of T1D in HLAA* 0201-transgenic NOD mice. Aim 2a. To target preproinsulin to DCs via DEC-205 and monitor the response of endogenous CD8+ and CD4+ insulin-specific T cells in HLA-A*0201-transgenic NOD mice. Aim 2b. To test the efficacy of preproinsulin targeting to DCs for the prevention of T1D in HLAA* 0201-transgenic NOD mice. Aim 3. To determine whether human islet-reactive T cells can be tolerized in response to DEC- 205-mediated delivery of β cell antigens to DCs. Aim 4. To determine the mechanisms responsible for the T cell tolerance observed in response to DEC-205-mediated delivery of β cell antigens to dendritic cells.

1型糖尿病（T1D）是一种自身免疫性疾病，其特征是T细胞介导的破坏 胰岛胰岛细胞。点头小鼠构成了一个广泛研究的模型，用于共享许多 人类疾病的特征。我们对t的至少一些靶向的β细胞抗原的了解 现在，NOD小鼠和T1D患者的细胞实际上都可以用于开发基于抗原的策略 干扰致病性自动反应性T细胞群体，以更好地理解和增强自然 公差诱导途径。树突状细胞（DC）对于启动自适应免疫反应至关重要 致病。然而，在稳态中，DC以耐受性的方式向T细胞呈现抗原，并且是 对于建立外围耐受性很重要。虽然知道这是这种情况 我们最近不容易发展自身免疫性，而是在一个环境中评估了这一概念 自发性免疫性疾病。我们提供了一种模仿肽，该肽通过糖尿病生成的糖尿病识别 CD8+ T细胞克隆AI4，使用对DC内吞的肽连接抗体的NOD小鼠的DC 受体DEC-205。最初观察到转移的抗原特异性T细胞的增殖，但这是 其次是删除。因此，DCS的选择性抗原靶向导致删除转移的自动反应性 CD8+ T细胞即使是在具有已知耐受性缺陷的NOD小鼠中持续的自身免疫性的背景下。尽管 有希望的，必须在适用此类调查之前进行大量额外调查 T1D患者的技术。我们的目标是以逐步的方式将这种策略移至人道化 与T1D患者相关性增加的小鼠模型。提出了四个具体目标： 目标1a。确定β细胞抗原的CD8+ T细胞表位是否靶向稳态 通过DEC-205的DC可以导致HLA-A*0201-中内源性抗原特异性T细胞的缺失。 转基因点头小鼠。 目标1B。测试抗原靶向DC的功效，以预防HLAA* 0201-Transgenic Nod小鼠。 目标2a。通过DEC-205靶向前胰岛素对DC并监测内源性的响应 HLA-A*0201-转基因NOD小鼠中的CD8+和CD4+胰岛素特异性T细胞。 目标2B。测试前硫蛋白靶向DC的疗效，以预防HLAA*中T1D的疗效 0201-Transgenic Nod小鼠。 目的3。确定是否可以根据DEC-耐受性胰岛反应性T细胞 205介导的β细胞抗原向DC递送。 目标4。确定负责T细胞耐受性的机制 至DEC-205介导的β细胞抗原向树突状细胞的递送。