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: 6270794
• 负责人: CLYDE F BARKER
• 金额: $ 12.85万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-06-01 至 1999-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6270794
• 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）对于合理的治疗是必要的 设计预防和治疗的具体疗法 糖尿病。然而，成功的免疫疗法可预防 IDDM 要求鉴定涉及的相关靶抗原 自身免疫过程。当前的提案旨在探索一些新颖的 预防和治疗自身免疫性疾病的治疗策略 NOD 小鼠患有糖尿病。该提案有三个主要目标： 首先，IDDM 的非肥胖糖尿病 (NOD) 小鼠模型将 纵向探索对两种主要的耐受性的自发丧失 分子水平上推定的自身抗原。我们将利用重叠 谷氨酸脱羧酶 65 (GAD) 和胰岛素肽测定 胰岛来源的 T 细胞的免疫原性和特异性。分子 T 细胞表达的细胞因子 mRNA 转录水平分析 对自身抗原作出反应将引出有关 T 的明确数据 自身免疫性疾病发生和进展所必需的辅助子集 糖尿病。此外，我们建议评估其致糖尿病的潜力 GAD 和胰岛素肽反应性胰岛来源的 T 细胞通过执行 对 NOD scid/scid 受体的过继转移实验。最后，我们 提议使用基因治疗新技术来表达 免疫调节蛋白可以改善免疫系统的脆弱性 胰岛反复发生自身免疫性破坏。 在具体目标 2 中，我们建议检查胸腺内的潜力 接种骨髓和胰岛细胞以“拯救”免受破坏 NOD 小鼠中残留的胰腺 b 细胞。此外，这些接种物 还将用于促进捐助者对具体问题的不反应 长期糖尿病 NOD 小鼠的胸腺外胰岛同种异体移植物。此外， 我们建议开发大型动物模型用于临床前评估 人类胸腺介导的免疫耐受的潜力。 具体目标3，白细胞跨内皮迁移的机制 及其在白细胞募集至胰岛中的作用 将研究环境。我们建议评估阻塞的潜力 血小板内皮细胞粘附分子-1 (PECAM-1) 治疗 糖尿病发生过程。我们还试图研究 CD4-的机制 介导的信号转导及其在激活中的作用 自身抗原特异性 T 细胞。通过利用新型 CD4 环状类似物， 我们寻求通过以下方式治疗和预防自身免疫性糖尿病的发作 以抗原特异性方式阻断自身免疫反应。此外， 我们将利用从特定目标 1 获得的信息来创建 新型糖基化肽，具有更高的稳定性和 肽特异性抑制自身抗原反应性 T 细胞的潜力 方式。