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（T1 D）是一种自身免疫性疾病，其特征在于T细胞介导的对糖尿病细胞的破坏。 胰岛细胞NOD小鼠构成了广泛研究的T1 D模型， 人类疾病的特征。我们对T细胞靶向的至少一些细胞抗原的了解， NOD小鼠和T1 D患者的细胞现在可以实际用于开发基于抗原的策略， 干扰致病性自身反应性T细胞群，并更好地了解和增强自然免疫。 耐受诱导途径树突状细胞（DC）是启动适应性免疫应答的关键 病原体。然而，在稳定状态下，DC以致耐受性方式向T细胞呈递抗原， 这对建立外周耐受性很重要。虽然这是已知的情况下，在小鼠， 不倾向于自身免疫的发展，我们最近评估了这个概念的设置， 自发性自身免疫性疾病我们递送了一种模拟表位肽，其被糖尿病NOD衍生的 CD 8 + T细胞克隆AI 4与NOD小鼠中的DC结合，使用DC内吞肽的肽连接抗体。 受体DEC-205。最初观察到转移的抗原特异性T细胞的增殖，但这是不可能的。 然后删除。因此，DC的选择性抗原靶向导致转移的自身反应性T细胞的缺失。 CD 8 + T细胞，即使在具有已知耐受缺陷的NOD小鼠中持续自身免疫的背景下。而 在应用这种方法之前，必须进行大量的额外调查。 T1 D患者的技术。我们的目标是逐步将这一策略人性化 与T1 D患者相关性增加的小鼠模型。提出了四个具体目标： 目标1a。确定细胞抗原的CD 8 + T细胞表位是否靶向稳态 DC通过DEC-205可导致HLA-A*0201- 0205中内源性抗原特异性T细胞的缺失。 转基因NOD小鼠。 目标1b。测试靶向DC的抗原用于预防HLAA* 中的T1 D的功效 0201-转基因NOD小鼠。 目标2a。通过DEC-205将前胰岛素原靶向DC，并监测内源性胰岛素原的反应。 HLA-A*0201转基因NOD小鼠中的CD 8+和CD 4+胰岛素特异性T细胞。 目标2b。测试靶向DC的前胰岛素原预防HLAA* 中T1 D的功效 0201-转基因NOD小鼠。 目标3。为了确定人类胰岛反应性T细胞是否可以响应于DEC而耐受， 205-介导的细胞抗原向DC的递送。 目标4。确定在应答中观察到的T细胞耐受的机制， 涉及DEC-205介导的细胞抗原向树突细胞的递送。