REGULATORY MECHANISMS IN TYPE I DIABETES

I 型糖尿病的调节机制

• 批准号: 6702198
• 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/6702198
• 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：（改编自研究者摘要）：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）小鼠发生糖尿病 这与人类相似。据推测， 胸腺选择过程和抗原特异性 自身反应性Th 1细胞在NOD小鼠中，但在 在自身免疫性糖尿病中起着关键作用。NOD小鼠表达一种疾病 相关的MHC II类I-Ag 7，必须存在于两个等位基因中 对于糖尿病的发展。了解各种自身抗原 表位可以选择自身反应性T细胞，并且检测和 糖尿病性T细胞的特征应该有助于我们确定 调节机制导致糖尿病和设计治疗性治疗。 在上一个应用阶段，我们成功地产生了自身抗原 特异性I-Ag 7四聚体以检测T细胞。主要目标是 应用是继续我们的研究，以检测和表征T细胞的 使用I-Ag 7四聚体的不同抗原特异性，并确定其 在糖尿病发展中的作用。有三个具体目标： 特定目标A被设计为使用可用的I-Ag 7四聚体来分离和 表征自身反应性T细胞。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，额外的I-Ag 7四聚体 将产生对其它自身抗原肽具有特异性的抗体。这些研究 可以帮助我们确定是否有不同抗原的自身反应性T细胞 特异性可能在糖尿病中发挥不同的作用。在具体目标C中， 将进行实验以分离和比较自身反应性T细胞与 NOD小鼠与疾病T细胞的抗原特异性相同 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与疾病抗性小鼠中产生的机制。 整体拟议的研究应有助于我们确定不同的作用， 自身抗原肽和自身反应性T细胞，以及调节机制 导致疾病的潜在免疫反应。