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: 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
• 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

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(申请人提供)：1型糖尿病(T1D)是一种以T细胞介导的胰岛β细胞破坏为特征的自身免疫性疾病。我们对NOD小鼠模型和T1D患者中T细胞靶向的至少部分β细胞抗原的了解，现在可以用于开发基于抗原的策略，以干扰致病T细胞群，并增强自然耐受诱导途径。我们假设，治疗T1D的有效免疫治疗策略是消除针对重要β细胞抗原的致病CD8+和CD4+T细胞，同时促进调节性T细胞(Treg)的扩张，从而能够控制针对各种β细胞抗原的剩余致病T细胞。我们将利用我们在使用针对树突状细胞(DC)内分泌受体DEC-205的抗原连接抗体将抗原靶向树突状细胞(DC)方面的经验来开发这样一种方法。当抗原在没有佐剂的情况下以这种方式递送时，DC以耐受性的方式递送它们，并导致原始T细胞被删除、变得无反应或被赋予调节特性。使用我们最近生产的一种试剂，我们建议将β细胞抗原原传递给DC，并确定这种治疗对致病CD8+和CD4+T细胞的影响以及对Treg的诱导。这些研究将使用我们开发的基于NOD的小鼠模型(命名为NOD.22mnull.HHD.Ins2+/-)，该模型转基因表达与T1D相关的人类HLA-A*0201，并且Ins2基因敲除等位基因也是杂合子，导致胸腺胰岛素表达减少，从而模拟大多数T1D患者的情况。还将使用包含人类细胞的最先进的老鼠模型。最后，我们的实验系统将是确定靶向DC的抗原诱导T细胞耐受的理想途径。提出了三个特定的目标：(1)通过DEC-205将胰岛素原靶向DC，并监测其对NOD.22mnull.HHD.Ins2+/-小鼠T细胞和T1D的影响；(2)确定人胰岛反应性T细胞是否可以耐受DEC-205介导的向DC传递β细胞抗原；(3)确定在DEC-205介导的向DC传递β细胞抗原的反应中观察到的T细胞耐受的重要途径。我们提出的研究将对T1D抗原特异性疗法的发展具有重要意义，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。