REGULATORY MECHANISMS IN TYPE I DIABETES

I 型糖尿病的调节机制

• 批准号: 6628086
• 负责人: CHIH-PIN LIU
• 金额: $ 39.38万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-01 至 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6628086
• 关键词: MHC class I antigen; NOD mouse; T cell receptor; T lymphocyte; autoantigens; cellular pathology; glutamate decarboxylase; insulin dependent diabetes mellitus; interferon gamma; interleukin 4; laboratory mouse; leukocyte activation /transformation

DESCRIPTION: (Adapted from the Investigator's abstract): Type 1 diabetes is a T cell mediated autoimmune disease. Nonobese diabetic (NOD) mice develop diabetes that is similar to that in human. It is hypothesized that a breakdown in the thymus selection process and a biased development of antigen specific autoreactive Th1 cells in NOD mice, but not in disease resistant strains of mice, plays a critical role in autoimmune diabetes. NOD mice express a disease associated MHC Class II I-Ag7 that is necessary to be present in both alleles for diabetes development. An understanding of how various autoantigenic epitopes may select for autoreactive T cells, and detection and characterization of diabetogenic T cells should help us to determine the regulatory mechanisms leading to diabetes and to design therapeutic treatments. During the last application period, we have successfully generated autoantigen specific I-Ag7 tetramers to detect T cells. The major goals for this application are to continue our studies to detect and characterize T cells of different antigen specificities using I-Ag7 tetramers, and to determine their role in diabetes development. There are three specific aims: Experiments in Specific Aim A are designed to use the available I-Ag7 tetramers to isolate and characterize autoreactive T cells. The studies will allow us to determine if these cells can cause diabetes and to characterize their functions, such as their cytokine secretion pattern. In Specific Aim B, additional I-Ag7 tetramers specific for other autoantigenic peptides will be generated. These studies should help us to determine if autoreactive T cells with different antigen specificities may play varying roles in diabetes. In Specific Aim C, experiments will be performed to isolate and compare autoreactive T cells with the same antigen specificities from NOD mice with T cells from disease resistant strains. These experiments should allow us to understand the mechanisms of how autoreactive T cells arise in NOD vs. disease resistant mice. The overall proposed studies should help us to determine the roles of different autoantigenic peptides and autoreactive T cells, and regulatory mechanisms underlying immune responses leading to the disease.

描述：(改编自研究人员摘要)：1型糖尿病是一种T 细胞介导的自身免疫性疾病。非肥胖糖尿病(NOD)小鼠发展为糖尿病 这与人类的情况相似。据推测，美国经济的崩溃 胸腺选择过程与抗原特异性的偏向发展 NOD小鼠中的自身反应性Th1细胞，但在抗病品系中不存在 小鼠在自身免疫性糖尿病中起着关键作用。NOD小鼠表现出一种疾病 在两个等位基因中都必须存在的相关MHC II类I-Ag7 用于糖尿病的发展。对各种自身抗原性的理解 表位可选择为自身反应性T细胞，并检测和 糖尿病T细胞的特征应该有助于我们确定 导致糖尿病的调控机制和设计治疗方法。 在上一次应用期间，我们成功地产生了自身抗原 特异性I-Ag7四聚体检测T细胞。这方面的主要目标是 应用是继续我们的研究，以检测和表征T细胞 用I-Ag7四聚体检测不同抗原的特异性 在糖尿病发展中的作用。有三个具体目标：在 特定目标A旨在利用可用的I-Ag7四聚体分离和 确定自身反应性T细胞的特征。这些研究将使我们能够确定 这些细胞可以引起糖尿病，并表征它们的功能，例如 它们的细胞因子分泌模式。在特定目标B中，增加I-Ag7四聚体 将产生其他自身抗原肽的特异性。这些研究 应该有助于我们确定不同抗原的自身反应性T细胞 特异性可能在糖尿病中扮演不同的角色。在特定目标C中， 将进行实验分离自身反应性T细胞并将其与 NOD小鼠与疾病T细胞具有相同的抗原特异性 耐药菌株。这些实验应该能让我们理解 自身反应性T细胞如何在NOD与抗病小鼠中产生的机制。 整体拟议的研究应有助于我们确定不同的 自身抗原肽和自身反应性T细胞及其调节机制 导致这种疾病的潜在免疫反应。