ENDOTOXIN TOLERANCE AS A MODEL FOR IMMUNE PARALYSIS

内毒素耐受作为免疫麻痹的模型

• 批准号: 6511013
• 负责人: FREDERICK P. HEINZEL
• 金额: $ 25.8万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-15 至 2004-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6511013
• 关键词: apoptosis; bacteria infection mechanism; biomarker; blood toxicology; candidiasis; cellular immunity; clinical research; disease /disorder model; endotoxins; heart /lung bypass; human subject; immune tolerance /unresponsiveness; immunoregulation; interferon gamma; interleukin 12; laboratory mouse; natural killer cells; nosocomial infections; pathologic process; postoperative complications; prognosis; tumor necrosis factor alpha

DESCRIPTION (adapted from applicant's abstract) The applicants propose to study the pathogenesis and biologic significance of injury-induced defects in the innate cellular immune response. These include studies of both experimental endotoxin tolerance in mice and clinical immune paralysis in cardiac surgery patients. Endotoxin tolerance is induced by repeated exposures to lipopolysaccharide (endotoxin) and results in reduced synthesis of pro-inflammatory cytokines to microbial stimuli. Immune paralysis is phenotypically similar, but is a clinical phenomenon induced by sepsis or trauma. They hypothesize that endotoxin tolerance and immune paralysis disrupt the interdependent production and synergistic anti-microbial activities of TNF-alpha, IL-12 and IFN-gamma that mediate the innate cellular immune response. Their first goal is to use the well-characterized mouse model of endotoxin tolerance to identify mechanisms that mediate the immune defects of endotoxin tolerance and enhance susceptibility to infection. They will then identify interventions that prevent or reverse these immune deficiencies. Preliminary data already indicate immune cell depletion is a mechanism for injury-induced cytokine deficiency and identify a 10- to 10,000-fold enhanced susceptibility to candidiasis during endotoxin tolerance. The applicants' second goal is to study the biologic basis and epidemiologic consequence of immune paralysis in cardiac surgery patients, with a long term goal of developing clinical interventions to prevent immune paralysis. The specific aims of this proposal are: 1) Identify molecular and/or cellular defects in the innate immune response of endotoxin tolerant mice. 2) Determine if the defective innate immunity of endotoxin tolerance enhances susceptibility to common nosocomial pathogens. 3) Use these findings to rationally design drug or cytokine therapies that prevent the immune defects of endotoxin tolerance and thereby reduce susceptibility to nosocomial superinfection. 4) Characterize comparable cytokine and cellular defects in hospitalized patients following cardiac surgery and identify immune phenotypic markers predictive of post-operative infections. Studies of the immune pathogenesis of infectious susceptibility in endotoxin tolerant mice are likely to suggest cytokine- or anti-apoptosis-based therapies for clinical immune paralysis. This is a clinically desirable goal, as the preservation or enhancement of innate immunity against nosocomial infections in injured patients may significantly reduce hospital morbidity, costs, antibiotic use and the selection of antibiotic-resistant pathogens.

说明(摘自申请人的摘要)申请人拟攻读 兔膝关节损伤后缺陷的发生机制及生物学意义 先天细胞免疫反应。这些研究包括对两种实验的研究 小鼠内毒素耐受与心脏外科临床免疫麻痹 病人。内毒素耐受性是由反复暴露于 脂多糖(内毒素)，并导致合成减少 促炎细胞因子对微生物刺激的作用。免疫性瘫痪是 表型相似，但这是一种由脓毒症或 精神创伤。他们假设内毒素耐受性和免疫麻痹会破坏 黄曲霉毒素的相互依赖生产及协同抗菌活性 介导先天细胞免疫的肿瘤坏死因子-α、白细胞介素12和干扰素-γ 回应。他们的第一个目标是使用特征良好的小鼠模型 内毒素耐受以确定介导免疫缺陷的机制 内毒素耐受性和对感染的易感性。到时候他们就会 确定预防或逆转这些免疫缺陷的干预措施。 初步数据已经表明，免疫细胞耗尽是一种 损伤诱导的细胞因子缺乏症并鉴定10至10,000倍的增强 内毒素耐受期间对念珠菌病的易感性。申请人的 第二个目标是研究红斑狼疮的生物学基础和流行病学后果。 心脏手术患者的免疫瘫痪，长期目标是 开发预防免疫性瘫痪的临床干预措施。具体的 这项建议的目的是：1)识别分子和/或细胞缺陷 内毒素耐受小鼠的先天免疫反应。2)确定是否 内毒素耐受的先天免疫缺陷增加了易感性 常见的医院病原菌。3)利用这些发现合理设计药物或 预防内毒素耐受和免疫缺陷的细胞因子治疗 从而降低对医院内双重感染的易感性。4)描述 术后住院患者细胞因子和细胞缺陷的可比性 心脏手术和识别免疫表型标志物预测 手术后感染。传染性支气管炎免疫发病机制的研究进展 内毒素耐受小鼠的易感性可能表明细胞因子-或 以抗细胞凋亡为基础的临床免疫麻痹治疗。这是一个 临床上理想的目标，如保留或增强先天的 损伤患者对医院感染的免疫力可能显著 减少医院发病率、成本、抗生素的使用和选择 抗药性病原体。