Brucella, Aging and Role of IL-17 in Host Defense

布鲁氏菌、衰老和 IL-17 在宿主防御中的作用

基本信息

批准号：
6909967
负责人：
KEVIN P. HIGH
金额：
$ 25.94万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-01 至 2007-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6909967
关键词：
Brucella age difference antigen presenting cell bacteria infection mechanism clinical research cytokine disease /disorder model helper T lymphocyte human old age (65+)human subject immune response immunoregulation immunosenescence laboratory mouse patient oriented research young adult human (21-34)

项目摘要

DESCRIPTION (provided by applicant): Adults over the age of 65 comprise the fastest growing segment of the U.S. population. Aging increases susceptibility to most intracellular microbes (e.g. Mycobacterium, Salmonella, influenza and other viruses), likely due to waning immunity with advanced age termed 'immune senescence'. Immune senescence is characterized by impaired Th1 immunity, and efforts to reverse the responses that wane in immune senescence have been largely unsuccessful. However, recent data suggest augmenting immune responses that remain intact, even in far advanced age, may be a more achievable strategy to reduce the burden of infectious diseases in older adults. Brucella spp., important causes of disease in both human and animals, represent an exception to the rule that age increases the risk of infection due to intracellular pathogens. Scant published literature and our preliminary experiments suggest older adult mice and humans are no more susceptible to Brucella infection, and may in fact be less susceptible to this pathogen. In this proposal, we will use murine models to explore the immune mechanisms that remain intact or are enhanced with age, that allow efficient clearance of Brucella infection. Our preliminary data demonstrate marked increases in the poorly studied T cell cytokine IL-17 in response to whole Brucella organisms and specific Brucella antigens, particularly in older mice when compared to young adult mice. We suspect that the enhanced resistance of older adult mice may be due to IL-17, and the first aim of this proposal is to better define this association across the age spectrum. Very recent data have suggested IL-17 responses may be mediated by the antigen presenting cell-derived cytokine IL-23. This recently discovered feedback loop at the innate/adaptive interface may be an IL-12 independent mechanism to activate Th1 immune responses, a critical need to enhance resistance to intracellular pathogens in older adults. Initial investigations in this regard form the basis of our second aim. Finally, we will determine the clinical relevance of IL-17 in host defense by blocking the activity of this cytokine in murine models of brucellosis, and assessing the presence of IL-17 secreting memory T cells in humans with active or past Brucella infection. The data generated in this proposal will form the foundation of future R01 proposals aimed at enhancing immunity vs. intracellular pathogens in our aging population.

描述（由申请人提供）：65 岁以上的成年人是美国人口中增长最快的群体。衰老增加了对大多数细胞内微生物（例如分枝杆菌、沙门氏菌、流感和其他病毒）的易感性，这可能是由于随着年龄的增长免疫力下降，称为“免疫衰老”。免疫衰老的特点是 Th1 免疫力受损，扭转免疫衰老中减弱的反应的努力基本上不成功。然而，最近的数据表明，增强即使在高龄时仍保持完整的免疫反应可能是减轻老年人传染病负担的更可行的策略。布鲁氏菌是人类和动物疾病的重要原因，它代表了年龄增加细胞内病原体感染风险这一规则的例外。很少发表的文献和我们的初步实验表明，老年小鼠和人类不再容易受到布鲁氏菌感染，而且实际上可能不太容易受到这种病原体的影响。在本提案中，我们将使用小鼠模型来探索保持完整或随着年龄的增长而增强的免疫机制，从而有效清除布鲁氏菌感染。我们的初步数据表明，研究不足的 T 细胞因子 IL-17 对整个布鲁氏菌生物体和特定布鲁氏菌抗原的反应显着增加，特别是与年轻成年小鼠相比，老年小鼠。我们怀疑老年小鼠抵抗力增强可能是由于 IL-17，该提案的首要目的是更好地定义跨年龄范围的这种关联。最近的数据表明 IL-17 反应可能是由抗原呈递细胞衍生的细胞因子 IL-23 介导的。最近发现的先天/适应性界面的反馈回路可能是激活 Th1 免疫反应的独立于 IL-12 的机制，这是增强老年人对细胞内病原体的抵抗力的关键需要。这方面的初步调查构成了我们第二个目标的基础。最后，我们将通过在布鲁氏菌病鼠模型中阻断IL-17这种细胞因子的活性，并评估患有活动性或既往布鲁氏菌感染的人类中IL-17分泌记忆T细胞的存在，来确定IL-17在宿主防御中的临床相关性。该提案中生成的数据将构成未来 R01 提案的基础，旨在增强老龄化人口中针对细胞内病原体的免疫力。