NOVEL IMMUNOMODULATORY STRATEGIES FOR PREVENTION AND TREATMENT OF DIABETES

预防和治疗糖尿病的新型免疫调节策略

• 批准号: 6105702
• 负责人: CLYDE F BARKER
• 金额: $ 13.77万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-15 至 2000-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6105702
• 关键词: CD4 molecule; NOD mouse; T lymphocyte; autoantigens; cell adhesion molecules; cell migration; cytokine; diabetes mellitus therapy; glutamate decarboxylase; immune tolerance /unresponsiveness; immunomodulators; immunotherapy; insulin; insulin dependent diabetes mellitus; leukocyte activation /transformation; pancreatic islet transplantation; thymus

Cellular and molecular characterization of the immune pathogenesis of insulin-dependent diabetes mellitus (IDDM) is necessary for the rational design of specific therapies for the prevention and treatment of diabetes. However, successful immunotherapy for the prevention of IDDM mandates identification of the relevant target antigen(s) involved in the autoimmune process. This current proposal seeks to explore several novel therapeutic strategies for the prevention and treatment of autoimmune diabetes in the NOD mouse. There are three major aims of this proposal: First, the non-obese diabetic (NOD) murine model of IDDM will be longitudinally probed for a spontaneous loss of tolerance to two major putative autoantigens at a molecular level. We will utilize overlapping glutamic acid decarboxylase-65 (GAD) and insulin peptides to determine the immunogenicity and specificity of islet-derived T cells. Molecular analysis of cytokine mRNA transcript levels elaborated by T cells responsive to autoantigens will elicit definitive data regarding the T helper subset requisite for the onset and progression of autoimmune diabetes. Furthermore, we propose to evaluate the diabetogenic potential of GAD and insulin peptide-reactive islet-derived T cells by performing adoptive transfer experiments to NOD scid/scid recipients. Finally, we propose to use the novel technique of gene therapy to express immunomodulatory proteins which can ameliorate the vulnerability of islets to recurrent autoimmune destruction. In specific aim 2, we propose to examine the potential of intrathymic inocula of bone marrow and islet cells for "rescue" from the destruction of residual pancreatic b-cells in the NOD mouse. Moreover, these inocula will also e used to promote donor-specific unresponsiveness to extrathymic islet allografts in long-term diabetic NOD mice. Furthermore, we propose to develop a large animal model for the preclinical evaluation of the potential of thymus-mediated immune tolerance in man. In specific aim 3, the mechanisms of leukocyte transendothelial migration and their role in the recruitment of leukocytes to the pancreatic islet milieu will be studied. We propose to assess the potential of blocking platelet endothelial cell adhesion molecule-1 (PECAM-1) to treat the diabetogenic process. We also seek to examine the mechanisms of CD4- mediated signal transduction and its role in the activation of autoantigen-specific T cells. By utilizing a novel CD4 cyclic analogue, we seek to both treat and prevent the onset of autoimmune diabetes by blocking autoimmune responses in an antigen-specific manner. Furthermore, we will utilize the information obtained from Specific Aim 1 to create novel glycosylated peptides which have increased stability and the potential to suppress autoantigen-reactive T cells in an peptide-specific manner.

免疫发病机制的细胞和分子特征 胰岛素依赖型糖尿病（IDDM）是必要的， 设计预防和治疗 糖尿病然而，成功的免疫疗法预防胰岛素依赖型糖尿病 要求鉴定参与免疫应答的相关靶抗原。 自身免疫过程目前的建议旨在探索几种新颖的 预防和治疗自身免疫性疾病的治疗策略 NOD小鼠的糖尿病这项建议有三个主要目的： 首先，非肥胖糖尿病（NOD）小鼠模型的胰岛素依赖型糖尿病将是 纵向探测对两种主要的耐受性的自发丧失 分子水平上的自身抗原我们将利用重叠 谷氨酸脱羧酶-65（GAD）和胰岛素肽，以确定 胰岛来源的T细胞的免疫原性和特异性。分子 T细胞加工的细胞因子mRNA转录水平的分析 对自身抗原的反应将引出关于T细胞的明确数据， 自身免疫性疾病发生和发展所必需的辅助细胞亚群 糖尿病此外，我们建议评估糖尿病的潜力， GAD和胰岛素肽反应性胰岛衍生的T细胞， NOD scid/scid受体的过继转移实验。最后我们 建议使用基因治疗的新技术来表达 免疫调节蛋白，可以改善脆弱性， 胰岛复发性自身免疫性破坏。 在具体目标2中，我们建议检查胸腺内注射的潜力。 骨髓和胰岛细胞的接种，用于从破坏中“拯救” NOD小鼠体内残留的胰腺B细胞。此外，这些接种物 也将被用来促进捐助方对以下方面的反应迟钝： 长期糖尿病NOD小鼠的胸腺外胰岛同种异体移植物。此外，委员会认为， 我们建议开发一个大型动物模型进行临床前评估 胸腺介导的免疫耐受的潜力。 在具体目标3中，白细胞跨内皮迁移的机制 以及它们在白细胞向胰岛募集中的作用 环境将被研究。我们建议评估封锁的可能性 血小板内皮细胞粘附分子-1（PECAM-1）治疗 致糖尿病过程我们还试图研究CD 4- 介导的信号转导及其在激活 自身抗原特异性T细胞。通过利用新的CD 4环状类似物， 我们寻求治疗和预防自身免疫性糖尿病的发病， 以抗原特异性方式阻断自身免疫反应。此外，委员会认为， 我们将利用从具体目标1获得的信息， 具有增加的稳定性的新型糖基化肽， 抑制自身抗原反应性T细胞在肽特异性 方式