Subversion T Cell Response by A. actinomycetemcomitans

A. actinomycetemcomitans 颠覆 T 细胞反应

• 批准号: 6747959
• 负责人: HOMAYOUN H ZADEH
• 金额: $ 27.58万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-03-15 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6747959
• 关键词: Actinobacillus actinomycetemcomitans; SDS polyacrylamide gel electrophoresis; antigen antibody reaction; antigen presenting cell; apoptosis; bacteria infection mechanism; clinical research; cytotoxicity; enzyme linked immunosorbent assay; flow cytometry; host organism interaction; human subject; immunofluorescence technique; immunosuppression; interleukin 1; interleukin 10; leukocyte activation /transformation; nucleic acid purification; patient oriented research; periodontitis; polymerase chain reaction; suppressor T lymphocyte; terminal nick end labeling; tissue /cell culture; transforming growth factors; western blottings

DESCRIPTION (provided by applicant): Aa is a major pathogen implicated in several forms of periodontal diseases, and non-oral infections. Despite extensive investigation, the exact mechanism of pathogenicity of this microorganism remains obscure, though it is believed that the host mediates much of it. There is evidence that this bacterium uses a number of mechanisms to evade the host response. Recent studies in our laboratory have demonstrated that Aa induces a very potent T cell activation response. While up to two-third of all T cells are activated, they exhibit impaired cytokine expression and the majority undergoes apoptosis. The few T cells that do express cytokines, predominantly express IL-10, which has immunosuppressive effects. Many periodontitis patients fail to mount an effective antibody response against periodontal pathogens. Based on data, we have posited that Aa interferes with antigen-specific T cell response by large-scale antigen nonspecific activation. The activated cells include regulatory T cells that suppress the antigen-specificT cell response. We further posit that the Aa cytotoxins kill the majority of T cells by apoptosis. To investigate our hypothesis, we have proposed Specific Aims to: 1) characterize the cellular and molecular mediators of T cell apoptosis; 2) examine the nature of the suppression induced by regulatory T cells and 3) identify and characterize the functional attributes of Aa-specific T cells found in periodontitis sites. The characterization of Aa-mediated immunosuppression will not only aid in understanding of the mechanism of pathogenicity of this organism, but it may offer additional experimental tools for manipulating the T cell response. There is currently great need for developing immunosuppressive tools for therapy of autoimmune diseases and prevention of graft rejection.

描述（由申请人提供）：Aa 是与多种形式的牙周病和非口腔感染有关的主要病原体。尽管进行了广泛的研究，但这种微生物致病性的确切机制仍然不清楚，尽管人们相信宿主介导了其中的大部分。有证据表明这种细菌使用多种机制来逃避宿主反应。我们实验室最近的研究表明，Aa 可诱导非常有效的 T 细胞激活反应。虽然多达三分之二的 T 细胞被激活，但它们表现出细胞因子表达受损，并且大多数会发生凋亡。少数表达细胞因子的 T 细胞主要表达具有免疫抑制作用的 IL-10。许多牙周炎患者未能针对牙周病原体产生有效的抗体反应。根据数据，我们假设 Aa 通过大规模抗原非特异性激活来干扰抗原特异性 T 细胞反应。激活的细胞包括抑制抗原特异性T细胞反应的调节性T细胞。我们进一步推测 Aa 细胞毒素通过凋亡杀死大多数 T 细胞。为了研究我们的假设，我们提出了具体目标：1）表征 T 细胞凋亡的细胞和分子介质； 2) 检查调节性 T 细胞诱导的抑制的性质，3) 识别和表征牙周炎部位发现的 Aa 特异性 T 细胞的功能属性。 Aa 介导的免疫抑制的表征不仅有助于了解该生物体的致病机制，而且可能为操纵 T 细胞反应提供额外的实验工具。目前非常需要开发免疫抑制工具来治疗自身免疫性疾病和预防移植排斥。