T-cell Co-stimulation in Obesity-induced Inflammation and Atherosclerosis

T 细胞协同刺激治疗肥胖引起的炎症和动脉粥样硬化

基本信息

批准号：
8507992
负责人：
Vince N Montes
金额：
$ 13.54万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8507992
关键词：
Adipocytes Adipose tissue Anti-Inflammatory Agents Anti-inflammatory Antibodies Antigen Presentation Antigen-Presenting Cells Antigens Arterial Fatty Streak Arteries Atherosclerosis B7-2 protein Binding Blocking Antibodies CD28 gene CD4 Positive T Lymphocytes CD40 Ligand CD80 gene CD8B1 gene CTLA4-Ig Cardiovascular Diseases Cause of Death Cell Membrane Proteins Cells Characteristics Cholesterol Coculture Techniques Control Animal Data Dendritic Cells Development Diet Disease Ensure Environment Evaluation FDA approved Fatty Acids Flow Cytometry Gene Expression Gene Expression Profiling Goals Helper-Inducer T-Lymphocyte High Density Lipoproteins Human Immune response Immune system In Vitro Individual Inflammation Inflammatory Insulin Resistance Intervention Knockout Mice Lead Link Lipids Low Density Lipoprotein Receptor MHC Class II Genes Mentors Metabolic Metabolic Diseases Methods Mus Natural Immunity Obesity Ovum Pathway interactions Phenotype Physicians Plasma Polyunsaturated Fatty Acids Process Property Proteins Research Research Personnel Resources Risk Factors Role Saturated Fatty Acids Scientist Specific qualifier value Stimulus Structure Surface T-Cell Activation T-Cell Proliferation T-Cell Receptor T-Lymphocyte TNFRSF5 gene Testing Therapeutic Time Undifferentiated Universities Washington abstracting adaptive immunity career development cell type cytokine feeding glucose tolerance immunogenic improved insulin tolerance killer T cell lymphocyte proliferation macrophage neutralizing antibody prevent programs response saturated fat vascular inflammation

项目摘要

DESCRIPTION (provided by applicant): Obesity is an underlying risk factor for atherosclerosis and obesity-associated metabolic disorders. Inflammation has been linked as a key to both these processes. We seek to understand the role of T cells, of the adaptive immune system in these inflammatory processes. With respect to atherosclerosis, activated T cells have been found in human atherosclerotic plaques. We plan to evaluate the role of T cell activation in both adipose tissue and arterial wall inflammation by interfering with their activation by inhibiting tw distinct pathways of T cell co-stimulation. T cells are activated in a two-step process, initially involving T cell receptor- antigen recognition, and then activation of the CD80/86-CD28 pathway. Other co-stimulatory pathways that may be synergistic include the CD40-CD40L pathway. T cell activation is highly dependent on the co- stimulatory actions of these pathways. The CD80/86-CD28 pathway can be inhibited by CTLA-4 Ig, or abatacept, an FDA- approved biologic agent. The CD40-CD40L pathway can be inhibited by a neutralizing antibody to CD40 ligand (CD40L). Although blocking the CD40/CD40L pathway with an anti-CD40L antibody has been shown to ameliorate atherosclerosis, the effects of CTLA-4 Ig alone and in conjunction with anti- CD40L antibody on atherosclerosis have not been studied. Since the combination of CTLA-4 Ig and anti- CD40L antibody is a validated method of inducing tolerance in adaptive immune responses, it is important to test this combination in the setting of obesity-associated inflammation and atherosclerosis. The goal of this proposal is to evaluate the effects of these agents alone and in combination in the development of adipose tissue inflammation and atherosclerosis in mice. We plan on using LDL receptor knockout (Ldlr-/-) mice on the C57BL/6 background. These mice are susceptible to adipose tissue inflammation, insulin resistance and atherosclerotic lesion development when placed on a diet that resembles the typical Western diet that is high in saturated fat and cholesterol. In addition, we plan to evaluate the effects of fatty acids and HDL on T cell proliferation in vitro, which can lead to identification of mechanisms of adaptive immune response modulation by these molecules. Also, our preliminary in vitro data suggest a unique property of pre-adipocytes to develop molecules required for professional antigen presentation. We will expand these studies to confirm and identify the significance of this finding. Elucidating important pathways and agents that can mitigate the development of adipose tissue inflammation, insulin resistance and atherosclerosis may lead to further interventions for these conditions in humans. These projects will be part of a structured mentored career development program that will culminate in my becoming an independent investigator as a physician-scientist. My mentor and co- mentors have developed a plan to ensure that I attain my goals within the specified time frame of this opportunity. The research environment at the University of Washington is excellent for a budding physician- scientist, and I plan on taking absolute advantage of the resources available. (End of Abstract)

描述（由申请人提供）：肥胖是动脉粥样硬化和肥胖相关代谢紊乱的潜在危险因素。炎症被认为是这两个过程的关键。我们试图了解 T 细胞和适应性免疫系统在这些炎症过程中的作用。关于动脉粥样硬化，在人类动脉粥样硬化斑块中发现了活化的 T 细胞。我们计划通过抑制 T 细胞共刺激的两种不同途径来干扰 T 细胞激活，从而评估 T 细胞激活在脂肪组织和动脉壁炎症中的作用。 T 细胞的激活分两步过程，首先涉及 T 细胞受体-抗原识别，然后激活 CD80/86-CD28 途径。其他可能具有协同作用的共刺激途径包括 CD40-CD40L 途径。 T 细胞的激活高度依赖于这些途径的共刺激作用。 CD80/86-CD28 通路可以被 CTLA-4 Ig 或阿巴西普（FDA 批准的生物制剂）抑制。 CD40-CD40L 途径可以被 CD40 配体 (CD40L) 的中和抗体抑制。尽管已显示用抗CD40L抗体阻断CD40/CD40L途径可改善动脉粥样硬化，但尚未研究单独使用CTLA-4 Ig以及与抗CD40L抗体联合使用对动脉粥样硬化的影响。由于 CTLA-4 Ig 和抗 CD40L 抗体的组合是诱导适应性免疫反应耐受的有效方法，因此在肥胖相关炎症和动脉粥样硬化的情况下测试这种组合非常重要。该提案的目的是评估这些药物单独和联合使用对小鼠脂肪组织炎症和动脉粥样硬化发展的影响。我们计划在 C57BL/6 背景上使用 LDL 受体敲除 (Ldlr-/-) 小鼠。当这些小鼠的饮食类似于典型的富含饱和脂肪和胆固醇的西方饮食时，它们很容易出现脂肪组织炎症、胰岛素抵抗和动脉粥样硬化病变的发展。此外，我们计划评估以下措施的影响：脂肪酸和高密度脂蛋白对体外 T 细胞增殖的影响，这可以导致识别这些分子调节适应性免疫反应的机制。此外，我们的初步体外数据表明前脂肪细胞具有开发专业抗原呈递所需分子的独特特性。我们将扩大这些研究以证实和确定这一发现的重要性。阐明可以减轻脂肪组织炎症、胰岛素抵抗和动脉粥样硬化发展的重要途径和药物可能会导致对人类这些疾病的进一步干预。这些项目将成为结构化指导职业发展计划的一部分，该计划最终将使我成为一名独立研究者，成为一名医师科学家。我的导师和同事制定了一个计划，以确保我在这个机会的指定时间范围内实现我的目标。华盛顿大学的研究环境对于崭露头角的医师科学家来说非常好，我计划充分利用可用的资源。（摘要完）