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: 8535749
• 负责人: Teresa P DiLorenzo
• 金额: $ 35.14万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-20 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8535749
• 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; Immune response; Immunotherapeutic agent; Inbred NOD Mice; Infection; Insulin; Insulin-Dependent Diabetes Mellitus; Intervention; Islets of Langerhans; Knock-out; 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; autoreactive T cell; base; experience; islet; meetings; mortality; mouse model; novel; pathogen; peripheral tolerance; response; treatment effect

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 β 细胞破坏。我们对 NOD 小鼠模型和 T1D 患者中 T 细胞靶向的至少一些 β 细胞抗原的了解现在可实际用于开发基于抗原的策略，以干扰致病性 T 细胞群并增强自然耐受诱导途径。我们假设 T1D 的有效免疫治疗策略是消除对重要 β 细胞抗原具有特异性的致病性 CD8+ 和 CD4+ T 细胞，同时促进调节性 T 细胞 (Treg) 的扩增，该细胞能够控制针对多种 β 细胞抗原的剩余致病性 T 细胞。我们将利用我们在使用针对 DC 内吞受体 DEC-205 的抗原联抗体将抗原靶向树突状细胞 (DC) 方面的经验来开发这种方法。当在没有佐剂的情况下以这种方式递送抗原时，DC 以致耐受的方式呈递它们，并导致幼稚 T 细胞被删除、变得无反应或被赋予调节性。 特征。使用我们最近生产的试剂，我们建议将 β 细胞抗原胰岛素原递送至 DC，并确定这种治疗对致病性 CD8+ 和 CD4+ T 细胞以及 Treg 诱导的影响。这些研究将采用我们开发的基于 NOD 的小鼠模型（指定为 NOD.22mnull.HHD.Ins2+/-），该模型转基因表达 T1D 相关的人类 HLA-A*0201，并且也是 Ins2 敲除等位基因的杂合子，导致胸腺胰岛素表达减少，因此模拟了大多数 T1D 患者的情况。还将采用结合人类细胞的最先进的小鼠模型。最后，我们的实验系统将非常适合确定将抗原靶向 DC 从而诱导 T 细胞耐受的途径。提出了三个具体目标：（1）通过 DEC-205 将胰岛素原靶向 DC，并监测其对 T 细胞的影响以及 NOD.22mnull.HHD.Ins2+/- 小鼠中 T1D 的发展； (2) 确定人胰岛反应性 T 细胞是否可以耐受 DEC-205 介导的 β 细胞抗原向 DC 的递送； (3) 确定对于响应 DEC-205 介导的 β 细胞抗原向 DC 递送而观察到的 T 细胞耐受性的重要途径。我们提出的研究将对 T1D 抗原特异性疗法的开发产生重要影响，并将提供有助于指导该疾病免疫调节疗法未来发展的信息。