Active tolerosomes, a novel therapy for type 1 diabetes

活性耐受体，一种治疗 1 型糖尿病的新疗法

• 批准号: 7027696
• 负责人: HOWARD W DAVIDSON
• 金额: $ 14.77万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7027696
• 关键词: CD95 molecule; NOD mouse; apoptosis; chimeric proteins; diabetes mellitus therapy; drug design /synthesis /production; helper T lymphocyte; immune tolerance /unresponsiveness; insulin dependent diabetes mellitus; molecular cloning; nonhuman therapy evaluation; receptor binding; recombinant proteins; therapy design /development

DESCRIPTION (provided by applicant): Type 1 diabetes mellitus and its associated complications are a major health problem in the US. The disease, which originates from a breakdown in T-cell tolerance, has a significant pre-diabetic stage, during which effected individuals are essentially asymptomatic. This provides a window of opportunity for therapeutic intervention. Our aim is to generate an immune-based therapy that will selectively target the pathogenic cells without causing a global disturbance of the immune system. Productive interactions between T-cells and their targets are typically characterized by the formation of an "immune synapse" containing combinations of both clonotypic and oligotypic receptor-ligand pairs. Our central hypothesis is that antigen-specific therapy will require reagents which can mimic these events. As part of normal homeostatic mechanisms, T-cells stimulated through their antigen receptors can undergo activation induced apoptosis. This preferentially occurs to the potentially diabetogenic Th1 population, and is believed to be defective in at least some diabetic individuals due to a failure to induce pro-apoptotic molecules to sufficient levels. We will create synthetic antigen-specific pro-apoptotic molecules predicted to restore this functional deficit in vivo. These novel reagents should induce apoptosis of the targeted (pathogenic) cells, but spare potentially protective ones, and may therefore lead to a change in the immune balance, and tolerance. We will test this hypothesis using established model systems. The project will involve three phases. 1. The creation of single chain peptide-MHC class II complexes and chimeras with Fas ligand by molecular cloning techniques. 2. In vitro analysis of the reagents using a panel of antigen-specific T-cell clones, and primary cells isolated from transgenic, pre-diabetic or newly diabetic NOD mice. 3. Analysis of the reagents in vivo following adoptive transfer of diabetogenic cells into NOD/SCI mouse models of diabetes. Ultimately we envisage that this novel strategy will form the basis for improved therapies for pre-diabetic or newly diabetic human subjects.

描述（由申请人提供）：1型糖尿病及其相关并发症是美国的主要健康问题。该疾病起源于T细胞耐受性的崩溃，具有明显的糖尿病前期，在此期间，受影响的个体本质上是无症状的。这为治疗干预提供了机会窗口。我们的目的是产生一种免疫治疗，该治疗将有选择地靶向病原细胞，而不会引起对免疫系统的全球性干扰。 T细胞及其靶标之间的生产性相互作用通常以“免疫突触”形成，其中包含clonotypic和寡型受体配体对的组合。我们的中心假设是，抗原特异性治疗将需要可以模仿这些事件的试剂。作为正常稳态机制的一部分，通过其抗原受体刺激的T细胞会受到激活诱导的凋亡。这优先发生在潜在的糖尿病性TH1群体上，并且由于未能将促凋亡分子诱导到足够的水平，因此人们认为至少在某些糖尿病患者中是有缺陷的。我们将创建合成的抗原特异性促凋亡分子，预计将恢复体内这种功能不足。这些新型试剂应诱导靶向（致病性）细胞的凋亡，但可能具有潜在保护性的细胞，因此可能导致免疫平衡和耐受性发生变化。我们将使用已建立的模型系统检验这一假设。该项目将涉及三个阶段。 1。通过分子克隆技术创建具有FAS配体的单链肽MHC II类配合物和嵌合体。 2。使用一组抗原特异性T细胞克隆和从转基因，糖尿病前或新糖尿病的NOD小鼠分离的原代细胞对试剂的体外分析。 3。分析糖尿病细胞转移到糖尿病的点头/SCI小鼠模型之后，对体内的试剂分析。 最终，我们设想这种新型策略将构成改善糖尿病前期或新糖尿病人类受试者疗法的基础。