Mechanisms of Innate Immune Memory

先天免疫记忆的机制

• 批准号: 7770417
• 负责人: MEGAN Anne COOPER
• 金额: $ 12.01万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-03 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7770417
• 关键词: Academic Medical Centers; Activities of Daily Living; Address; Adoptive Transfer; Antigens; Area; B-Lymphocytes; Bacterial Infections; Cell Differentiation process; Cells; Characteristics; Childhood; Cytokine Activation; Data; Defect; Disease; Epigenetic Process; Exhibits; Genes; Genetic Transcription; Goals; Immune; Immune response; Immune system; Immunocompromised Host; Immunologic Memory; Immunologist; In Vitro; Infection; Interferons; Lead; Listeria monocytogenes; Longevity; Lymphocyte; Mediating; Memory; Mentors; Mentorship; Messenger RNA; Modification; Murid herpesvirus 1; Mutation; NK Cell Activation; Natural Immunity; Natural Killer Cells; Patients; Physicians; Physiological; Production; Property; Proteins; Recording of previous events; Regulation; Research; Scientist; Specificity; System; Training; Translations; Universities; Viral; Virus Diseases; Washington; Work; adaptive immunity; arm; base; career development; clinically relevant; cytokine; cytotoxic; daughter cell; experience; improved; in vivo; killings; member; neonate; pathogen; programs; research study; response

DESCRIPTION (provided by applicant): This application proposes a 5 year program to provide the candidate with mentored scientific training and career development guidance. The long term goal of the candidate is to be an independent physician-scientist at an academic medical center, investigating the innate immune response and potential mechanisms of enhancing this immune system for the treatment of pediatric disease. The proposed work will be performed at Washington University in St. Louis under the mentorship of Dr. Wayne Yokoyama, an accomplished immunologist and physician-scientist. The immune response to infection is mediated by two broad arms, the innate and adaptive immune systems. One classical distinction between innate and adaptive immunity is the restriction of immunologic memory to adaptive T and B lymphocytes. Innate immune cells are a first-line defense against pathogens and are thought to respond consistently to infection, regardless of previous exposure, i.e., they do not exhibit memory of prior activation. Natural killer (NK) cells are innate lymphocytes capable of recognizing and killing target cells and producing immunoregulatory cytokines, especially IFN-?. NK cells are important for the initial control of a variety of pathogens, and defects in NK cells lead to uncontrolled, fatal infections. Preliminary studies utilizing an adoptive transfer system demonstrate that NK cells with a history of prior cytokine activation exhibit an NK-intrinsic, enhanced capacity to produce IFN-? upon re- stimulation. This "memory-like" property appears to be both stable and heritable. The proposed experiments will further characterize memory-like NK cells in vitro and in vivo and investigate the mechanisms of NK cell memory. The specific aims are to: (1) Determine the functional attributes of memory-like NK cells and if cytotoxic memory-like NK cells can be generated; (2) Determine if memory-like NK cells differentiate in vivo in response to pathogens; and (3) Determine if enhanced IFN-? production by memory-like NK cells is controlled transcriptionally, by epigenetic modifications, and/or post-transcriptionally. These studies have clinical relevance, since patients whose adaptive immune systems are immature or dysfunctional, such as neonates or immunocompromised patients, may benefit from augmentation of their intact innate immune NK cell response. Natural killer cells are a key component of the innate immune response and provide protection against a variety of infections. These experiments explore fundamental mechanisms by which natural killer cells and the innate immune system may be enhanced based on prior experiences. This area of research may lead to improved therapies to augment the immune response and treat infections.

描述（由申请人提供）：本申请提出了一项为期5年的计划，以向候选人提供指导的科学培训和职业发展指导。候选人的长期目标是成为学术医学中心的独立医师科学家，研究先天免疫反应和增强这种免疫系统治疗儿科疾病的潜在机制。拟议的工作将在圣路易斯的华盛顿大学在韦恩·尤科亚山（Wayne Yokoyama）博士的指导下，是一位有成就的免疫学家和医师科学家。对感染的免疫反应是由两个宽臂（先天和适应性免疫系统）介导的。先天和适应性免疫之间的经典区别是免疫记忆对适应性T和B淋巴细胞的限制。先天免疫细胞是针对病原体的一线防御，被认为对感染的反应一致，无论先前的暴露如何，即它们没有表现出对先前激活的记忆。天然杀手（NK）细胞是能够识别和杀死靶细胞并产生免疫调节细胞因子的先天淋巴细胞，尤其是IFN-？ NK细胞对于多种病原体的初始控制很重要，NK细胞的缺陷导致致命的致命感染不受控制。使用收养转移系统的初步研究表明，具有先前细胞因子活化史的NK细胞表现出NK内部，增强产生IFN-的能力？刺激后。这种“记忆般的”属性似乎既稳定又可遗传。提出的实验将进一步表征体外和体内内存状的NK细胞，并研究NK细胞记忆的机制。具体目的是：（1）确定类似内存的NK细胞的功能属性以及是否可以生成细胞毒性内存样NK细胞； （2）确定记忆样的NK细胞是否响应病原体而在体内区分； （3）确定是否增强了IFN-？通过表观遗传修饰和/或转录后，通过记忆样的NK细胞的产生，可以通过转录进行转录。这些研究具有临床相关性，因为适应性免疫系统不成熟或功能失调的患者（例如新生儿或免疫功能低下的患者）可能会受益于增强其完整的先天免疫NK细胞反应的增强。天然杀伤细胞是先天免疫反应的关键组成部分，并提供了针对多种感染的保护。这些实验探讨了基本机制，根据先前的经验，可以通过这种机制来增强天然杀伤细胞和先天免疫系统。这一研究领域可能会改善疗法，以增加免疫反应并治疗感染。