Chemokine regulation of immune cell recruitment during Pneumocystis pneumonia

肺孢子虫肺炎期间免疫细胞募集的趋化因子调节

基本信息

  • 批准号:
    7207945
  • 负责人:
  • 金额:
    $ 37.87万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2006
  • 资助国家:
    美国
  • 起止时间:
    2006-04-01 至 2011-02-28
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Despite improved antiretroviral therapy, Pneumocystis carinii pneumonia (PcP) remains the most common AIDS-defining illness, and is a significant cause of AIDS-related morbidity and mortality. Recent studies have reported mortality rates as high as 50% for AIDS patients with severe PcP, and one study named PcP as the leading cause of death among HIV-infected patients. Importantly, the clinical severity of PcP correlates more closely with the level of inflammation than with organism burden, and using mouse models of AIDS-related PcP we have directly demonstrated that immune-mediated lung injury plays a central role in the pathophysiology of PcP. However, the mechanisms by which pathologic immune cells are recruited to the lung remain largely unknown. PC interacts closely with the alveolar epithelium (AECs), and this interaction results in the secretion of chemotactic factors called chemokines that could function to recruit damaging immune cells to the lung during PC infection. We hypothesize that AECs are critically involved in the pathway leading to immune-mediated lung injury during PcP, and that interrupting this pathway will alleviate lung injury and improve patient outcome. The Specific Aims of this proposal are designed to: 1) define the mechanism of Pc-stimulated chemokine production by AECs; 2) determine whether chemokine production by AECs modulates immune cell recruitment to the lung; 3) determine how chemokine receptor expression on responding immune cells affects their recruitment to the lung; and 4) determine whether therapeutic modulation of chemokine function alleviates PcP-related lung injury. We will use a combination of primary cell culture and chimeric knockout mouse models to definitively answer these questions. The long-term goals of this project are to understand the consequences of the Pc-AEC interaction for immune cell recruitment to the lung, and how this interaction may be exploited to alleviate inflammatory injury during PcP. PcP remains an important concern of the health care community. While the incidence of PcP has decreased due to antibiotic prophylaxis, it remains the most common AIDS-defining illness as well as a significant cause of disease and death in other immunocompromised patients such as those with cancer or who receive medications that suppress the immune system. Antibiotic treatment of PcP does not always result in immediate clinical improvement because the host's ongoing immune response is a major cause of PcP-related lung injury. Therefore the proposed studies are designed to increase our understanding of the mechanisms leading to PcP-related lung injury with the hope of identifying specific therapeutic targets.
描述(由申请人提供):尽管抗逆转录病毒治疗有所改善,但卡氏肺孢子虫肺炎(PcP)仍然是最常见的艾滋病定义疾病,并且是艾滋病相关发病率和死亡率的重要原因。最近的研究报告,艾滋病患者严重PcP的死亡率高达50%,一项研究将PcP列为艾滋病病毒感染者死亡的主要原因。重要的是,PcP的临床严重程度与炎症水平的相关性比与有机体负荷的相关性更密切,并且使用AIDS相关PcP的小鼠模型,我们直接证明了免疫介导的肺损伤在PcP的病理生理学中起着核心作用。然而,病理性免疫细胞被募集到肺部的机制在很大程度上仍然未知。PC与肺泡上皮细胞(AEC)密切相互作用,并且这种相互作用导致称为趋化因子的趋化因子的分泌,所述趋化因子可以在PC感染期间起到将损伤性免疫细胞募集到肺的作用。我们假设,AEC是关键参与的途径,导致免疫介导的肺损伤在PcP,并中断这一途径将减轻肺损伤和改善患者的结果。该提案的具体目的旨在:1)定义AEC产生Pc刺激的趋化因子的机制; 2)确定AEC产生的趋化因子是否调节免疫细胞向肺的募集; 3)确定响应免疫细胞上的趋化因子受体表达如何影响其向肺的募集; 4)确定趋化因子功能的治疗性调节是否减轻PcP相关肺损伤。我们将使用原代细胞培养和嵌合基因敲除小鼠模型的组合来明确回答这些问题。该项目的长期目标是了解Pc-AEC相互作用对肺免疫细胞募集的影响,以及如何利用这种相互作用减轻PcP期间的炎症损伤。PcP仍然是卫生保健界的一个重要关注点。虽然由于抗生素预防,PcP的发病率有所下降,但它仍然是最常见的艾滋病定义疾病,也是其他免疫功能低下患者(如癌症患者或接受抑制免疫系统药物治疗的患者)的疾病和死亡的重要原因。PcP的抗生素治疗并不总是导致立即的临床改善,因为宿主的持续免疫应答是PcP相关肺损伤的主要原因。因此,拟议的研究旨在增加我们对导致PcP相关肺损伤的机制的理解,并希望确定特定的治疗靶点。

项目成果

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Terry W Wright其他文献

Terry W Wright的其他文献

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{{ truncateString('Terry W Wright', 18)}}的其他基金

Novel mechanisms of Alveolar Macrophage-Dependent Antifungal Innate Immunity
肺泡巨噬细胞依赖性抗真菌先天免疫的新机制
  • 批准号:
    10311998
  • 财政年份:
    2020
  • 资助金额:
    $ 37.87万
  • 项目类别:
Novel mechanisms of Alveolar Macrophage-Dependent Antifungal Innate Immunity
肺泡巨噬细胞依赖性抗真菌先天免疫的新机制
  • 批准号:
    10536600
  • 财政年份:
    2020
  • 资助金额:
    $ 37.87万
  • 项目类别:
Novel mechanisms of Alveolar Macrophage-Dependent Antifungal Innate Immunity
肺泡巨噬细胞依赖性抗真菌先天免疫的新机制
  • 批准号:
    10083184
  • 财政年份:
    2020
  • 资助金额:
    $ 37.87万
  • 项目类别:
Reversing inhibitory receptor signaling for PcP Therapy
逆转 PcP 疗法的抑制性受体信号传导
  • 批准号:
    9243968
  • 财政年份:
    2016
  • 资助金额:
    $ 37.87万
  • 项目类别:
Reversing inhibitory receptor signaling for PcP Therapy
逆转 PcP 疗法的抑制性受体信号传导
  • 批准号:
    9062825
  • 财政年份:
    2016
  • 资助金额:
    $ 37.87万
  • 项目类别:
Targeting Inhibitory T cell Receptors for PcP Therapy
靶向抑制性 T 细胞受体进行 PcP 治疗
  • 批准号:
    8927877
  • 财政年份:
    2015
  • 资助金额:
    $ 37.87万
  • 项目类别:
Macrophage effector functions during respiratory fungal infection
呼吸道真菌感染期间巨噬细胞效应功能
  • 批准号:
    8273610
  • 财政年份:
    2012
  • 资助金额:
    $ 37.87万
  • 项目类别:
Macrophage effector functions during respiratory fungal infection
呼吸道真菌感染期间巨噬细胞效应功能
  • 批准号:
    8463611
  • 财政年份:
    2012
  • 资助金额:
    $ 37.87万
  • 项目类别:
Macrophage effector functions during respiratory fungal infection
呼吸道真菌感染期间巨噬细胞效应功能
  • 批准号:
    8837679
  • 财政年份:
    2012
  • 资助金额:
    $ 37.87万
  • 项目类别:
Macrophage effector functions during respiratory fungal infection
呼吸道真菌感染期间巨噬细胞效应功能
  • 批准号:
    8656803
  • 财政年份:
    2012
  • 资助金额:
    $ 37.87万
  • 项目类别:

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