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REGULATORY MECHANISMS IN TYPE I DIABETES

I 型糖尿病的调节机制

基本信息

批准号：
6846031
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
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-02-01 至 2007-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6846031
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

项目摘要

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，但在小鼠在自身免疫性糖尿病中发挥着关键作用。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。