SUPER ANTIGENS IN PERIODONTAL DISEASES

牙周疾病中的超级抗原

基本信息

  • 批准号:
    6164407
  • 负责人:
  • 金额:
    $ 11.08万
  • 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 2002-02-28
  • 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.
牙周致病菌的免疫调节作用与牙周炎的发生有关。 炎症性牙周病的发病机制。一类新的 微生物来源的T细胞有丝分裂原,称为超抗原(SAg), 最近被描述。SAg的独特之处在于它们激活并扩展 以抗原非依赖性的方式刺激大量T细胞亚群, 子集可以用区分 T细胞抗原可变区的不同亚型(家族) 受体(TCR V β. SAg被认为会导致免疫功能障碍, 通过大规模T细胞活化的疾病的数量,导致: 某些细胞因子水平极高, 抑制其他细胞因子,从而破坏正常的免疫调节 稳态和介导组织损伤; 2)多克隆B细胞活化, 3)激活和扩增静止的自身反应性T细胞,和4) 使得定向免疫应答效率较低。初步 研究表明:牙龈卟啉单胞菌和 伴放线菌在体外具有SAg特性,2)在大多数 牙周病患者,有一个过度的代表性的一些子集, 牙龈T细胞,以其TCR V β区表达为标志, 体内SAg刺激T细胞的标志之一。在一些 患者中,少数TCR V β家族占所有牙龈T细胞的近50%, 表明SAg构成T细胞活化的主要途径 和扩张。这种T细胞亚群的倾斜特别引人注目 在活化的T细胞中,表明这些T细胞在体内刺激 (most可能是SAG)。 因此,我们假设一些假定的 牙周病细菌产生超抗原, 大量的T细胞以抗原非依赖的方式。此外,委员会认为, 超抗原扩增的T细胞存在于牙周炎部位。到 研究我们的假设,我们已经制定了具体的目标:1) 确定牙龈卟啉单胞菌和伴放线放线放线菌是否确实可以 有资格成为SAG。这将通过调查关键属性来实现 利用体外小鼠和 人类系统。2)评价体内SAg刺激的T细胞的存在 牙周炎部位的亚群和3)纯化和表征P. gingivalis和A.伴放线菌相关SAg.如果我们的 这一假说得到证实,对该病的发病机制有重要意义 牙周炎,涉及初始Ag非依赖性激活, T细胞扩增,多克隆B细胞活化,失调的细胞因子 自身反应性T和B细胞的释放和产生。 此外,委员会认为, 鉴定TCR分子的结构域和细菌组分, 与它们相互作用,为设计新的免疫增强剂奠定基础 涉及这些分子的更特异性靶向的方法。

项目成果

期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Evidence for apoptosis of the majority of T cells activated in vitro with Actinobacillus actinomycetemcomitans.
大多数 T 细胞在体外被 Actinobacillus actinomycetemcomitans 激活发生凋亡的证据。
  • DOI:
    10.1034/j.1399-302x.2000.150504.x
  • 发表时间:
    2000
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Nalbant,A;Zadeh,HH
  • 通讯作者:
    Zadeh,HH
Actinobacillus actinomycetemcomitans induces apoptosis of T lymphocytes by the Fas and Fas ligand pathway.
Actinobacillus actinomycetemcomitans 通过 Fas 和 Fas 配体途径诱导 T 淋巴细胞凋亡。
  • DOI:
    10.1034/j.1399-302x.2002.170503.x
  • 发表时间:
    2002
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Nalbant,A;Zadeh,HH
  • 通讯作者:
    Zadeh,HH
Large-scale early in vitro response to actinobacillus actinomycetemcomitans suggests superantigenic activation of T-cells.
对伴放线放线杆菌的大规模早期体外反应表明 T 细胞的超抗原激活。
  • DOI:
    10.1177/00220345010800011101
  • 发表时间:
    2001
  • 期刊:
  • 影响因子:
    7.6
  • 作者:
    Zadeh,HH;Nalbant,A;Park,K
  • 通讯作者:
    Park,K
Despite large-scale T cell activation, only a minor subset of T cells responding in vitro to Actinobacillus actinomycetemcomitans differentiate into effector T cells.
尽管大规模 T 细胞激活,但只有一小部分 T 细胞在体外对伴放线放线杆菌做出反应,分化为效应 T 细胞。
  • DOI:
    10.1034/j.1600-0765.2000.035003127.x
  • 发表时间:
    2000
  • 期刊:
  • 影响因子:
    3.5
  • 作者:
    Zadeh,HH;Tanavoli,S;Haines,DD;Kreutzer,DL
  • 通讯作者:
    Kreutzer,DL
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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:
    $ 11.08万
  • 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:
    $ 11.08万
  • 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:
    $ 11.08万
  • 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:
    $ 11.08万
  • 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:
    $ 11.08万
  • 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:
    $ 11.08万
  • 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:
    $ 11.08万
  • 项目类别:
SUPER ANTIGENS IN PERIDONTAL DISEASES
牙周疾病中的超级抗原
  • 批准号:
    2882713
  • 财政年份:
    1996
  • 资助金额:
    $ 11.08万
  • 项目类别:

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