SUPER ANTIGENS IN PERIDONTAL DISEASES

牙周疾病中的超级抗原

基本信息

  • 批准号:
    2882713
  • 负责人:
  • 金额:
    $ 11.71万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    1996
  • 资助国家:
    美国
  • 起止时间:
    1996-03-15 至 2001-02-28
  • 项目状态:
    已结题

项目摘要

Immunomodulation by periodontopathic bacteria has been implicated in the pathogenesis of inflammatory periodontal diseases. A novel class of microbial-derived T cell mitogens, referred to as superantigens (SAg), has recently been described. SAg are unique in that they activate and expand large subsets of T cells in an antigen-independent manner, and these subsets can be identified with reagents that discriminate between different subtypes (families) of the variable domain of T cell antigen receptor (TCR Vbeta. SAg are believed to cause immune dysfunction in a number of diseases by large-scale T cell activation, leading to: l) elaboration of overwhelmingly high levels of some cytokines, and depression of other cytokines, thereby disrupting normal immunoregulatory homeostasis and mediating tissue injury; 2) polyclonal B cell activation, 3) activation and expansion of quiescent autoreactive T cells, and 4) rendering the directed immune response less efficient. In preliminary studies, we have demonstrated that: P. gingivalis and A.actinomycetemcomitans have SAg properties in vitro and 2) in most periodontal patients, there is an overrepresentation of some subsets of gingival T cells, marked by their TCR Vbeta region expression, which is one of the hallmarks of in vivo SAg stimulation of T cells. In some patients, a few TCR Vbeta families comprised nearly 50% of all gingival T cells suggesting that SAg constitute a major pathway of T cell activation and expansion. This skewing of T cell subsets was particularly striking among activated T cells, suggesting in vivo stimulation of those T cells (most likely by SAg). Hence, we hypothesize that some of the putative periodontopathic bacteria produce superantigens that activate and expand a large number of T cells in a antigen-independent fashion. Moreover, superantigen-expanded T cells are present in periodontitis sites. To investigate our hypothesis, we have developed specific aims to: 1) determine whether P. gingivalis and A.actinomycetemcomitans can indeed qualify as SAg. This will be accomplished by investigating key properties that distinguish SAg from conventional Ag, utilizing in vitro murine and human systems. 2) Evaluate the existence of in vivo SAg-stimulated T cell subsets in periodontitis sites and 3) purify and characterize P. gingivalis- and A. actinomycetemcomitans -associated SAg. If our hypothesis is confirmed, it has important implications on the pathogenesis of periodontitis, involving initial Ag-independent activation and expansion of T cells, polyclonal B-cell activation, dysregulated cytokine release and generation of autoreactive T and B cells. Furthermore, identifying domains of the TCR molecules and the bacterial components that interact with them, lays the foundation for devising new immunoerapeutic approaches involving more specific targeting of these molecules.
牙周病细菌的免疫调节作用与 炎症性牙周病的发病机制。一类新奇的 微生物衍生的T细胞有丝分裂原,称为超抗原(SAG),具有 最近被描述过。SAG的独特之处在于它们可以激活和扩展 T细胞的大亚群以不依赖于抗原的方式,这些 子集可以用区分以下各项的试剂进行识别 T细胞抗原可变区的不同亚型(家族) 受体(TCR VBeta.SAG被认为会导致免疫功能障碍 疾病多由T细胞大规模激活,导致:L) 阐述了一些细胞因子的极高水平,以及 抑制其他细胞因子,从而扰乱正常的免疫调节 动态平衡和介导组织损伤;2)多克隆B细胞激活, 3)静止的自身反应性T细胞的激活和扩增;4) 从而降低了定向免疫反应的效率。在预赛中 研究表明:牙龈假单胞菌和 放线菌伴生菌在体外具有SAG特性,2)在大多数 牙周患者,存在某些亚群的过度表达 牙周T细胞,以其TCR Vbeta区表达为标志,这是 体内SAG刺激T细胞的标志之一。在一些 患者中,少数TCR Vbeta家族占所有牙龈T细胞的近50% 细胞提示SAG是T细胞活化的主要途径 和扩张。T细胞亚群的这种倾斜尤其令人震惊 在激活的T细胞中,表明这些T细胞在体内被刺激 (最有可能是SAG)。因此,我们假设一些假定的 牙周病细菌产生可激活和扩展的超抗原 大量的T细胞以非抗原依赖的方式存在。此外, 超抗原扩增的T细胞存在于牙周炎部位。至 调查我们的假设,我们制定了具体的目标:1) 确定牙龈假单胞菌和伴生放线菌是否真的可以 符合SAG的资格。这将通过调查关键属性来实现 将SAG与常规抗原区分开来,利用体外小鼠和 人类系统。2)评估体内SAG刺激的T细胞的存在 牙周炎部位的亚群;3)纯化和鉴定P。 伴生放线菌与牙龈杆菌相关的SAG。如果我们的 假说得到证实,对发病机制有重要意义。 牙周炎,涉及最初的银非依赖性激活和 T细胞扩增、多克隆B细胞活化、细胞因子失调 自身反应性T细胞和B细胞的释放和生成。此外, 鉴定TCR分子的结构域和细菌成分 与他们互动,为设计新的免疫疗法奠定基础 涉及到更具体地针对这些分子的方法。

项目成果

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HOMAYOUN H ZADEH其他文献

HOMAYOUN H ZADEH的其他文献

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{{ truncateString('HOMAYOUN H ZADEH', 18)}}的其他基金

SUPER ANTIGENS IN PERIDONTAL DISEASES
牙周疾病中的超级抗原
  • 批准号:
    2668247
  • 财政年份:
    1996
  • 资助金额:
    $ 11.71万
  • 项目类别:
Subversion T Cell Response by A. actinomycetemcomitans
A. actinomycetemcomitans 颠覆 T 细胞反应
  • 批准号:
    7072751
  • 财政年份:
    1996
  • 资助金额:
    $ 11.71万
  • 项目类别:
Subversion T Cell Response by A. actinomycetemcomitans
A. actinomycetemcomitans 颠覆 T 细胞反应
  • 批准号:
    6747959
  • 财政年份:
    1996
  • 资助金额:
    $ 11.71万
  • 项目类别:
SUPER ANTIGENS IN PERIDONTAL DISEASES
牙周疾病中的超级抗原
  • 批准号:
    2377648
  • 财政年份:
    1996
  • 资助金额:
    $ 11.71万
  • 项目类别:
SUPER ANTIGENS IN PERIODONTAL DISEASES
牙周疾病中的超级抗原
  • 批准号:
    6164407
  • 财政年份:
    1996
  • 资助金额:
    $ 11.71万
  • 项目类别:
Subversion T Cell Response by A. actinomycetemcomitans
A. actinomycetemcomitans 颠覆 T 细胞反应
  • 批准号:
    6893673
  • 财政年份:
    1996
  • 资助金额:
    $ 11.71万
  • 项目类别:
Subversion T Cell Response by A. actinomycetemcomitans
A. actinomycetemcomitans 颠覆 T 细胞反应
  • 批准号:
    6581505
  • 财政年份:
    1996
  • 资助金额:
    $ 11.71万
  • 项目类别:
SUPER ANTIGENS IN PERIDONTAL DISEASES
牙周疾病中的超级抗原
  • 批准号:
    2131775
  • 财政年份:
    1996
  • 资助金额:
    $ 11.71万
  • 项目类别:

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