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限制的天然杀伤细胞（NK T细胞）已被确定为调节性T细胞的关键群体，可控制自身免疫反应。这些细胞中的缺陷已被认为是人类和非肥胖糖尿病（NOD）小鼠中自身免疫性胰岛β细胞破坏进展的因素。一种称为KRN7000的合成糖脂，它是α-半乳糖苷神经酰胺（Alphagalcer）的一种形式，具有专门激活NK T细胞的能力。用这种化合物对NOD小鼠的治疗可以显着延迟或预防糖尿病。可用的数据表明，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还通过NK T细胞和二次刺激树突状细胞和天然杀伤细胞触发了Th1型细胞因子的产生。这可能会限制其在与有害Th1炎症反应（例如1型糖尿病）相关的疾病中的治疗功效。 Porcelli博士的实验室最近确定了刺激NK T细胞反应改变的字母类似物的结构类似物，例如Th2细胞因子没有并发Th1细胞因子的优先分泌。我们的中心假设是，刺激Th2细胞因子产生能力增强的字母类似物的类似物在预防糖尿病中的治疗疗效将比字母含量更大，并且在抑制cytotoxic的抑制（CTL）的一部分是应有的（至少是对等体类似物的有益效果）自动抗原。在这一合作伙伴关系中，首席研究人员（Porcelli和Dilorenzo博士）将共同努力，以确定NK T细胞中NK T细胞的糖脂激活剂，以有效地阻止或逆转1型小鼠模型中胰岛的自动免疫介导的胰岛的破坏。将分析这些糖脂改变自动反应性T细胞的曲目和效应子功能的机制，并开发优化这些潜在治疗剂在体内使用这些潜在治疗剂的治疗方案。因此，该项目将结合Dilorenzo博士在NOD模型中T细胞反应和疾病进展的既定专业知识与Porcelli博士在糖脂化学，CD1和NK T细胞生物学领域的专业知识。具体的目的是：（1）测试字母的新型类似物的能力，从而引起NK T细胞的反应改变了NOD小鼠中糖尿病的反应； （2）评估这些字母类似物在糖尿病点头小鼠中促进合成胰岛移植物存活的能力； （3）确定体内模拟处理对CD1D限制的NK T细胞的数量，分布和功能的影响； （4）评估字母类似物对糖尿病β细胞细胞毒性CD8+ T细胞的激活，扩展和分布的影响。