Subversion T Cell Response by A. actinomycetemcomitans

A. actinomycetemcomitans 颠覆 T 细胞反应

• 批准号: 6893673
• 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/6893673
• 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是一种主要的病原体，与几种形式的牙周疾病和非口腔感染有关。尽管进行了广泛的研究，但这种微生物的致病性确切机制仍然晦涩难懂，尽管据信宿主介导了很多。有证据表明该细菌使用多种机制来逃避宿主反应。我们实验室的最新研究表明，AA诱导了非常有效的T细胞激活反应。虽然最多三分之二的T细胞被激活，但它们表现出细胞因子表达受损，大多数会发生凋亡。确实表达细胞因子的少数T细胞主要表达IL-10，具有免疫抑制作用。许多牙周炎患者无法对牙周病原体进行有效的抗体反应。根据数据，我们认为AA通过大规模抗原非特异性激活干扰了抗原特异性T细胞反应。活化的细胞包括抑制抗原指细胞反应的调节性T细胞。我们进一步认为，AA细胞毒素通过细胞凋亡杀死了大多数T细胞。为了研究我们的假设，我们提出了特定的目的：1）表征T细胞凋亡的细胞和分子介质； 2）检查调节T细胞引起的抑制的性质，3）识别和表征牙周炎部位中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理解该生物的致病性机理，而且还可以提供其他实验工具来操纵T细胞反应。目前，需要开发用于治疗自身免疫性疾病和预防移植物排斥的免疫抑制工具。