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一个主要健康问题。这种疾病源于 T 细胞耐受性的破坏，有一个明显的糖尿病前期阶段，在此期间受影响的个体基本上没有症状。这为治疗干预提供了机会之窗。我们的目标是开发一种基于免疫的疗法，选择性地针对致病细胞，而不引起免疫系统的整体紊乱。 T 细胞与其靶标之间的生产性相互作用的典型特征是形成包含克隆型和寡型受体-配体对组合的“免疫突触”。我们的中心假设是抗原特异性疗法需要能够模拟这些事件的试剂。作为正常稳态机制的一部分，通过抗原受体刺激的 T 细胞可以经历激活诱导的细胞凋亡。这种情况优先发生在潜在的糖尿病性 Th1 群体中，并且据信至少在一些糖尿病个体中存在缺陷，因为未能诱导促凋亡分子达到足够的水平。我们将创建合成的抗原特异性促凋亡分子，预计可以在体内恢复这种功能缺陷。这些新型试剂应诱导目标（致病）细胞凋亡，但不影响潜在的保护性细胞，因此可能导致免疫平衡和耐受性的变化。我们将使用已建立的模型系统来测试这个假设。该项目将分为三个阶段。 1.通过分子克隆技术创建单链肽-MHC II类复合物以及与Fas配体的嵌合体。 2. 使用一组抗原特异性 T 细胞克隆和从转基因、糖尿病前期或新发糖尿病 NOD 小鼠中分离的原代细胞对试剂进行体外分析。 3.将致糖尿病细胞过继转移至糖尿病NOD/SCI小鼠模型后体内试剂分析。 最终，我们设想这种新策略将成为改善糖尿病前期或新糖尿病人类受试者治疗的基础。