ENDOTOXIN TOLERANCE AS A MODEL FOR IMMUNE PARALYSIS
内毒素耐受作为免疫麻痹的模型
基本信息
- 批准号:6362421
- 负责人:
- 金额:$ 25.8万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 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
项目摘要
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.
描述(改编自申请人的摘要)申请人建议研究
损伤性骨缺损的发病机制及其生物学意义
先天性细胞免疫反应这些研究包括两种实验性的
小鼠内毒素耐受与心脏手术中的临床免疫麻痹
患者内毒素耐受性是通过反复暴露于
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反应。免疫瘫痪是
表型相似,但是由败血症或
外伤他们假设内毒素耐受性和免疫麻痹会破坏
相互依赖的生产和协同的抗微生物活性,
TNF-α、IL-12和IFN-γ介导先天性细胞免疫
反应他们的第一个目标是使用特征良好的小鼠模型,
内毒素耐受性,以确定介导免疫缺陷的机制,
内毒素耐受性和增强对感染的易感性。然后他们将
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,免疫细胞耗竭是一种机制,
损伤诱导的细胞因子缺乏并确定增强10至10,000倍
内毒素耐受期间对念珠菌病的易感性。申请人的
第二个目标是研究生物学基础和流行病学后果,
心脏手术患者的免疫麻痹,长期目标是
开发临床干预措施以预防免疫瘫痪。具体
该建议的目的是:1)鉴定细胞中的分子和/或细胞缺陷,
内毒素耐受小鼠的天然免疫应答。2)确定是否
内毒素耐受性的先天免疫缺陷增强了对
常见的医院病原体。3)利用这些发现合理设计药物或
预防内毒素耐受性的免疫缺陷的细胞因子疗法,
从而降低对医院重复感染的易感性。4)表征
住院患者中的细胞因子和细胞缺陷相当,
心脏手术和识别免疫表型标志物预测
术后感染。传染性支气管炎免疫发病机制的研究
内毒素耐受小鼠易感性可能提示细胞因子或
临床免疫瘫痪的抗凋亡疗法。这是一
临床上理想的目标,如保留或增强先天性
受伤患者对医院感染的免疫力可能显着
减少住院发病率、费用、抗生素使用和
抗药性病原体。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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FREDERICK P. HEINZEL其他文献
FREDERICK P. HEINZEL的其他文献
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{{ truncateString('FREDERICK P. HEINZEL', 18)}}的其他基金
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:
6127300 - 财政年份:2000
- 资助金额:
$ 25.8万 - 项目类别:
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:
6632103 - 财政年份:2000
- 资助金额:
$ 25.8万 - 项目类别:
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 - 财政年份:2000
- 资助金额:
$ 25.8万 - 项目类别:
INTERLEUKIN-12 AS IMMUNOTHERAPY IN LEISHMANIASIS
INTERLEUKIN-12 作为利什曼病的免疫疗法
- 批准号:
2071988 - 财政年份:1994
- 资助金额:
$ 25.8万 - 项目类别:
INTERLEUKIN 12 FUNCTION DURING MURINE LEISHMANIASIS
鼠利什曼病期间白细胞介素 12 的功能
- 批准号:
2057400 - 财政年份:1994
- 资助金额:
$ 25.8万 - 项目类别:
INTERLEUKIN 12 FUNCTION DURING MURINE LEISHMANIASIS
鼠利什曼病期间白细胞介素 12 的功能
- 批准号:
2057399 - 财政年份:1994
- 资助金额:
$ 25.8万 - 项目类别:
INTERLEUKIN 12 FUNCTION DURING MURINE LEISHMANIASIS
鼠利什曼病期间白细胞介素 12 的功能
- 批准号:
2057398 - 财政年份:1994
- 资助金额:
$ 25.8万 - 项目类别:
INTERLEUKIN 12 AS IMMUNOTHERAPY IN LEISHMANIASIS
白细胞介素 12 作为利什曼病的免疫治疗
- 批准号:
6169986 - 财政年份:1994
- 资助金额:
$ 25.8万 - 项目类别:
INTERLEUKIN 12 AS IMMUNOTHERAPY IN LEISHMANIASIS
白细胞介素 12 作为利什曼病的免疫治疗
- 批准号:
2886914 - 财政年份:1994
- 资助金额:
$ 25.8万 - 项目类别:
INTERLEUKIN-12 AS IMMUNOTHERAPY IN LEISHMANIASIS
INTERLEUKIN-12 作为利什曼病的免疫疗法
- 批准号:
2071989 - 财政年份:1994
- 资助金额:
$ 25.8万 - 项目类别: