Role of CD8IL-13 T cells in Chlamydia infection-associated immunopathology

CD8IL-13 T 细胞在衣原体感染相关免疫病理学中的作用

基本信息

  • 批准号:
    9056430
  • 负责人:
  • 金额:
    $ 20.92万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-08-01 至 2018-03-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Chlamydia trachomatis genital tract infections have a prevalence of 2-15% in adolescents/young adults in the USA and Europe in spite of public health efforts and effective antibiotic therapy. It is widely accepted that a vaccine is necessary reduce its prevalence. An early C.trachomatis trachoma (eye infection) vaccine delivered poor protection and exacerbated immunopathology. Critical to developing a safe Chlamydia vaccine is a better understanding of immunopathology. Currently there are no practicable biomarkers for Chlamydia immunopathology. In the C. muridarum mouse model others have clearly shown that Chlamydia-specific CD8 T cells are important mediators of immunopathology and infertility. We have recently shown that a subset of Chlamydia-specific CD8 T cell clones derived from mice that self-cleared C. muridarum genital tract infections produce the scar-ogenic cytokines IL-10, TNF�nd IL-13. These CD8 clones are not restricted by MHC class Ia molecules. Similar non-class Ia restricted CD8 T cell clones have been derived from the peripheral blood of humans with C. trachomatis genital tract infections. Using gene expression microarray analysis we have identified a molecular fingerprint for CD8IL-13 T cells. Based on the existing mouse and human Chlamydia literature it clear that the cellular immune response to Chlamydia genital tract infections includes non-class Ia restricted CD8 T cells. The C. muridarum mouse model has unequivocally shown CD8 T cells to be mediators of immunopathology and infertility. We hypothesize that the mechanism underlying CD8 immunopathology is a non-MHC class Ia restricted CD8 T subset secreting IL-10, TNF�and IL-13. To test that hypothesis and investigate the underlying immunobiology we propose the following specific aims: Specific aim #1- to investigate the role of CD8IL-13 T cells in immunopathology utilizing adoptive transfer. We have representative conventional Chlamydia-specific CD8 T cell clones, Chlamydia-specific CD8IL-13 T cell clones, and putative cell surface biomarkers for purifying CD8IL-13 T cells from immune splenocytes or bulk T cell populations. Specific aim #2- to investigate the activation pathway and other immunobiology specific to Chlamydia-specific CD8IL-13 T cells. Utilizing existing T cell clones and gene expression microarray analysis we will compare activated conventional CD8 with activated CD8IL-13 T cells to identify CD8IL-13 specific immunobiology; potentially identifying additional biomarkers and targets for therapeutic intervention. We will als map the epitope source proteins for the Chlamydia-specific CD8 T cell clone panel. Specific aim #3- perform a preliminary investigation of CD8IL-13 T cells in humans. Using putative biomarkers for the CD8IL-13 T cell subset identified in the mouse model we will isolate CD8 T cells from the peripheral blood of healthy individuals and determine whether a similar CD8IL-13 T cell subset exists in humans.
描述(由申请人提供):尽管公共卫生努力和有效的抗生素治疗,在美国和欧洲的青少年/年轻人中,沙眼衣原体生殖道感染的患病率为2-15%。人们普遍认为疫苗是必要的,以减少其流行。早期沙眼原体(眼部感染)疫苗保护效果不佳,并加重了免疫病理。开发安全的衣原体疫苗的关键是更好地了解免疫病理学。目前还没有可行的衣原体免疫病理学生物标志物。在C. muridarum小鼠模型中,其他人已经清楚地表明衣原体特异性CD8 T细胞是免疫病理和不育的重要介质。我们最近的研究表明,来自自清除C. muridarum生殖道感染的小鼠的衣原体特异性CD8 T细胞克隆亚群产生疤痕源性细胞因子IL-10, TNF -和IL-13。这些CD8克隆不受MHC Ia类分子的限制。类似的非Ia类限制性CD8 T细胞克隆已从沙眼衣原体生殖道感染患者的外周血中获得。利用基因表达微阵列分析,我们已经鉴定出CD8IL-13 T细胞的分子指纹图谱。基于现有的小鼠和人类衣原体文献,清楚地表明,对衣原体生殖道感染的细胞免疫应答包括非Ia类限制性CD8 T细胞。C. muridarum小鼠模型明确显示CD8 T细胞是免疫病理和不育的介质。我们假设CD8免疫病理的机制是一个非mhc Ia类限制CD8 T亚群分泌IL-10、TNF -和IL-13。为了验证这一假设并研究潜在的免疫生物学,我们提出了以下具体目标:具体目标#1-利用过继性转移研究CD8IL-13 T细胞在免疫病理学中的作用。我们有代表性的传统衣原体特异性CD8 T细胞克隆,衣原体特异性CD8IL-13 T细胞克隆,以及用于从免疫脾细胞或散装T细胞群中纯化CD8IL-13 T细胞的假定的细胞表面生物标志物。特异性目的#2-研究衣原体特异性CD8IL-13 T细胞的激活途径和其他免疫生物学特异性。利用现有的T细胞克隆和基因表达微阵列分析,我们将比较活化的常规CD8和活化的CD8IL-13 T细胞,以鉴定CD8IL-13特异性免疫生物学;潜在地确定治疗干预的其他生物标志物和靶点。我们还将绘制衣原体特异性CD8 T细胞克隆面板的表位源蛋白。具体目标#3-对人类CD8IL-13 T细胞进行初步研究。利用在小鼠模型中鉴定的CD8IL-13 T细胞亚群的假定生物标志物,我们将从健康个体的外周血中分离CD8 T细胞,并确定人类中是否存在类似的CD8IL-13 T细胞亚群。

项目成果

期刊论文数量(1)
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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RAYMOND Morris JOHNSON其他文献

RAYMOND Morris JOHNSON的其他文献

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{{ truncateString('RAYMOND Morris JOHNSON', 18)}}的其他基金

Role of CD8IL-13 T cells in Chlamydia infection-associated immunopathology
CD8IL-13 T 细胞在衣原体感染相关免疫病理学中的作用
  • 批准号:
    8805282
  • 财政年份:
    2015
  • 资助金额:
    $ 20.92万
  • 项目类别:
Six new Chlamydia epitopes
六个新的衣原体表位
  • 批准号:
    8426077
  • 财政年份:
    2012
  • 资助金额:
    $ 20.92万
  • 项目类别:
Six new Chlamydia epitopes
六个新的衣原体表位
  • 批准号:
    8280847
  • 财政年份:
    2012
  • 资助金额:
    $ 20.92万
  • 项目类别:
Cellular Immunity to Chlamydua at the Epithelial Interface
上皮界面对衣原体的细胞免疫
  • 批准号:
    7900101
  • 财政年份:
    2009
  • 资助金额:
    $ 20.92万
  • 项目类别:
Cellular Immunity to Chlamydua at the Epithelial Interface
上皮界面对衣原体的细胞免疫
  • 批准号:
    7458802
  • 财政年份:
    2007
  • 资助金额:
    $ 20.92万
  • 项目类别:
Cellular Immunity to Chlamydua at the Epithelial Interface
上皮界面对衣原体的细胞免疫
  • 批准号:
    7640641
  • 财政年份:
    2007
  • 资助金额:
    $ 20.92万
  • 项目类别:
Cellular Immunity to Chlamydua at the Epithelial Interface
上皮界面对衣原体的细胞免疫
  • 批准号:
    7318666
  • 财政年份:
    2007
  • 资助金额:
    $ 20.92万
  • 项目类别:
Cellular Immunity to Chlamydua at the Epithelial Interface
上皮界面对衣原体的细胞免疫
  • 批准号:
    7883271
  • 财政年份:
    2007
  • 资助金额:
    $ 20.92万
  • 项目类别:
Immunobiology of Chlamydia
衣原体免疫生物学
  • 批准号:
    6736342
  • 财政年份:
    2002
  • 资助金额:
    $ 20.92万
  • 项目类别:
Immunobiology of Chlamydia
衣原体免疫生物学
  • 批准号:
    6647227
  • 财政年份:
    2002
  • 资助金额:
    $ 20.92万
  • 项目类别:

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