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

• 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
• 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

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（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细胞的作用，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，已在人动脉粥样硬化斑块中发现活化的T细胞。我们计划通过抑制两种不同的T细胞共刺激途径来干扰脂肪组织和动脉壁炎症中的T细胞活化，从而评估T细胞活化的作用。T细胞在两步过程中被激活，最初涉及T细胞受体-抗原识别，然后激活CD 80/86-CD 28途径。可以是协同的其他共刺激途径包括CD 40-CD 40 L途径。T细胞活化高度依赖于这些途径的共刺激作用。CD 80/86-CD 28通路可以被CTLA-4 IG或阿巴西普（FDA批准的生物制剂）抑制。CD 40-CD 40 L途径可被CD 40配体（CD 40 L）的中和抗体抑制。虽然用抗-CD 40 L抗体阻断CD 40/CD 40 L途径已显示改善动脉粥样硬化，但CTLA-4 IG单独和与抗-CD 40 L抗体联合对动脉粥样硬化的作用尚未研究。由于CTLA-4 IG和抗CD 40 L抗体的组合是在适应性免疫应答中诱导耐受性的经验证的方法，因此在肥胖相关炎症和动脉粥样硬化的情况下测试该组合是重要的。本提案的目标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C57 BL/6背景下使用LDL受体敲除（Ldlr-/-）小鼠。当这些小鼠被置于类似于饱和脂肪和胆固醇高的典型西方饮食的饮食中时，这些小鼠容易发生脂肪组织炎症、胰岛素抵抗和动脉粥样硬化病变发展。此外，我们计划评估 脂肪酸和HDL在体外对T细胞增殖的影响，这可以导致这些分子调节适应性免疫应答的机制的鉴定。此外，我们的初步体外数据表明，前脂肪细胞的独特性质，以开发专业抗原呈递所需的分子。我们将扩大这些研究，以确认和确定这一发现的意义。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。这些项目将是一个结构化的指导职业发展计划的一部分，这将最终使我成为一个独立的调查员作为一个医生，科学家。我的导师和同事们已经制定了一个计划，以确保我在这个机会的规定时间内实现我的目标。华盛顿大学的研究环境对一个初露头角的医生-科学家来说是极好的，我计划绝对利用现有的资源。(End摘要）