Prevention of Diabetes with Lipid Immunomodulators

用脂质免疫调节剂预防糖尿病

• 批准号: 6827490
• 负责人: Teresa P DiLorenzo
• 金额: $ 20.5万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6827490
• 关键词: NOD mouse; autoantigens; autoimmune disorder; cellular immunity; cytotoxic T lymphocyte; dendritic cells; disease /disorder prevention /control; glycolipids; helper T lymphocyte; immunomodulators; insulin dependent diabetes mellitus; interleukin 4; leukocyte activation /transformation; natural killer cells; pancreatic islets

DESCRIPTION (provided by applicant): In recent years, CD1d-restricted natural killer T cells (NK T cells) have been identified as a critical population of regulatory T cells that function to control autoimmune responses. Defects in these cells have been implicated as contributing factors in the progression of autoimmune islet beta cell destruction in type 1 diabetes, both in humans and in nonobese diabetic (NOD) mice. A synthetic glycolipid known as KRN7000, which is a form of alpha-galactosyl ceramide (alphaGalCer), has the capacity to specifically activate NK T cells. Treatment of NOD mice with this compound can significantly delay or prevent diabetes. Available data indicate that KRN7000 exerts its beneficial effects by stimulating NK T cells to produce protective Th2-type cytokines such as IL-4. However, KRN7000 also triggers production of Th1-type cytokines by NK T cells and by secondary stimulation of dendritic cells and natural killer cells. This could limit its therapeutic efficacy in diseases associated with a harmful Th1 inflammatory response such as type 1 diabetes. Dr. Porcelli's laboratory has recently identified structural analogues of alphaGalCer that stimulate altered responses of NK T cells, such as the preferential secretion of Th2 cytokines without concurrent Th1 cytokines. Our central hypothesis is that analogues of alphaGalCer that have an enhanced capacity to stimulate the production of Th2 cytokines will have an even greater therapeutic efficacy in diabetes prevention than alphaGalCer, and that the beneficial effects of alphaGalCer and its analogues are due at least in part to the suppression of cytotoxic T lymphocytes (CTL) specific for islet beta-cell autoantigens. In this collaborative partnership, the Principal Investigators (Drs. Porcelli and DiLorenzo) will work together to identify glycolipid activators of NK T cells that efficiently block or reverse the autoimmune-mediated destruction of pancreatic islets in the NOD mouse model of type 1 diabetes. The mechanisms by which these glycolipids alter the repertoire and effector functions of autoreactive T cells will be analyzed, and treatment protocols that optimize the use of these potential therapeutic agents in vivo will be developed. The project will thus combine Dr. DiLorenzo's established expertise in analysis of T cell responses and disease progression in the NOD model with Dr. Porcelli's expertise in the areas of glycolipid chemistry, CD1, and NK T cell biology. The Specific Aims are: (1) To test the ability of novel analogues of alphaGalCer that elicit altered response of NK T cells to prevent or reverse diabetes in NOD mice; (2) To assess the ability of these alphaGalCer analogues to promote syngeneic islet graft survival in diabetic NOD mice; (3) To determine the effects of in vivo analogue treatment on the numbers, distribution and functions of CD1d-restricted NK T cells; (4) To assess the effects of alphaGalCer analogues on the activation, expansion and distribution of diabetogenic beta-cell cytotoxic CD8+ T cells.

描述（由申请人提供）： 近年来，CD1d 限制性自然杀伤 T 细胞 (NK T 细胞) 已被确定为调节性 T 细胞的关键群体，其功能是控制自身免疫反应。这些细胞的缺陷被认为是人类和非肥胖糖尿病 (NOD) 小鼠 1 型糖尿病中自身免疫性胰岛 β 细胞破坏进展的促成因素。一种称为 KRN7000 的合成糖脂是 α-半乳糖神经酰胺 (alphaGalCer) 的一种形式，具有特异性激活 NK T 细胞的能力。用这种化合物治疗 NOD 小鼠可以显着延缓或预防糖尿病。现有数据表明，KRN7000 通过刺激 NK T 细胞产生保护性 Th2 型细胞因子（例如 IL-4）来发挥其有益作用。然而，KRN7000 还会触发 NK T 细胞以及树突状细胞和自然杀伤细胞的二次刺激产生 Th1 型细胞因子。这可能会限制其对与有害 Th1 炎症反应相关的疾病（例如 1 型糖尿病）的治疗效果。 Porcelli 博士的实验室最近发现了 alphaGalCer 的结构类似物，可以刺激 NK T 细胞改变反应，例如优先分泌 Th2 细胞因子，而不同时分泌 Th1 细胞因子。我们的中心假设是，具有增强的刺激 Th2 细胞因子产生能力的 alphaGalCer 类似物在预防糖尿病方面比 alphaGalCer 具有更大的治疗功效，并且 alphaGalCer 及其类似物的有益作用至少部分归因于抑制胰岛β细胞自身抗原特异性的细胞毒性T淋巴细胞（CTL）。在这一合作伙伴关系中，首席研究员（Porcelli 博士和 DiLorenzo 博士）将共同努力，鉴定 NK T 细胞的糖脂激活剂，该激活剂可有效阻止或逆转 1 型糖尿病 NOD 小鼠模型中自身免疫介导的胰岛破坏。我们将分析这些糖脂改变自身反应性 T 细胞的全部功能和效应器功能的机制，并开发优化这些潜在治疗剂在体内使用的治疗方案。因此，该项目将把 DiLorenzo 博士在 NOD 模型中 T 细胞反应和疾病进展分析方面的专业知识与 Porcelli 博士在糖脂化学、CD1 和 NK T 细胞生物学领域的专业知识结合起来。具体目标是： (1) 测试新型 alphaGalCer 类似物引发 NK T 细胞反应改变以预防或逆转 NOD 小鼠糖尿病的能力； (2) 评估这些 alphaGalCer 类似物促进糖尿病 NOD 小鼠同基因胰岛移植物存活的能力； (3) 确定体内类似物治疗对CD1d限制性NK T细胞数量、分布和功能的影响； (4) 评估 alphaGalCer 类似物对糖尿病性 β 细胞细胞毒性 CD8+ T 细胞的激活、扩增和分布的影响。