EFFECTS OF ASBESTOS ON T CELL ACTIVATION

石棉对 T 细胞激活的影响

• 批准号: 7720589
• 负责人: SCOTT Allen WETZEL
• 金额: $ 14.37万
• 依托单位: UNIVERSITY OF MONTANA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7720589
• 关键词: Address; Amphibole Asbestos; Antibodies; Asbestos; Asbestosis; B-Lymphocytes; Binding Proteins; CD4 Positive T Lymphocytes; CD8B1 gene; Cell membrane; Cells; Classification; Complex; Computer Retrieval of Information on Scientific Projects Database; Cytoplasmic Granules; Disease; Event; Exposure to; Fibrosis; Funding; Generations; Grant; Helper-Inducer T-Lymphocyte; Immune response; Immune system; Immunoglobulin Class Switching; Immunoglobulins; Institution; Ligands; Link; Location; Lymphocyte Activation; Mediator of activation protein; Mesothelioma; Mining; Molecular; Mus; Neoplastic Cell Transformation; Peptide/MHC Complex; Process; Pulmonary Fibrosis; Research; Research Personnel; Resources; Role; Serum; Signal Transduction; Site; Source; T-Cell Receptor; T-Lymphocyte; United States National Institutes of Health; cytokine; human disease; immune function; immunological synapse; segregation; synaptogenesis; vermiculite

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Asbestos exposure is linked with the induction of a variety debilitating and potentially fatal human diseases such as pulmonary fibrosis and mesothelioma. The mechanisms by which asbestos induces fibrosis and/or neoplastic transformation are unclear. Cytokines including TGF¿ and TNF¿ are critical mediators of asbestosis and mice lacking both TNFRI and TNFRII are not susceptible to asbestos induced pulmonary fibrosis. These findings suggest a role for the immune system in modulating asbestos-related diseases. A recent study from Pfau et al. identified immunological abnormalities in the residents of Libby, MT. Libby was contaminated with amphibole asbestos as a result of vermiculite mining and processing that took place between the early 1920's and 1990. Libby residents have increased serum Ig and elevated levels of auto-antibodies. Taken together, these findings strongly suggest that exposure to amphibole asbestos modulates immune function. To address the effects of amphibole asbestos on immune function this proposal focuses on the activation and differentiation of CD4+ T helper cells, a key event in the generation of an immune response. CD4+ T cells provide cytokine and contact-dependent help to B cells boosting immunoglobulin secretion and allowing for isotype switching. The interaction of a specific T cell antigen receptor (TCR) with the cognate MHC:peptide ligand on an APC rapidly initiates intracellular signaling. We and others have shown that this initial signaling leads to the large-scale redistribution of cytoplasmic and membrane-bound proteins to the site of T-APC interaction. These molecules are segregated both spatially and temporally into distinct regions within the interface called supramolecular activation complexes. The accumulation and segregation of these molecules leads to formation of the immunological synapse (IS). The IS is the location of sustained intracellular signaling necessary for full activation and differentiation to effector T cells. It is also the site of cytolytic granule release by CD8+ T cells and the location of secretion for a subset of effector cytokines by CD4+ T cells. The molecular constituents of the immunological synapse can have a significant impact on the activation state of the T cells. To date, no studies have undertaken a systematic approach to examine effects of amphibole asbestos on IS formation or T lymphocyte activation at the molecular level. In this proposal we will examine the formation and characterize the composition of the immunological synapse.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 砷暴露与诱发多种使人衰弱和可能致命的人类疾病有关，如肺纤维化和间皮瘤。石棉诱导纤维化和/或肿瘤转化的机制尚不清楚。细胞因子包括TGF？而TNF？是石棉沉着症的关键介质，缺乏TNFR 1和TNFRII的小鼠对石棉诱导的肺纤维化不敏感。这些发现表明免疫系统在调节石棉相关疾病中发挥着作用。Pfau等人最近的一项研究确定了蒙大拿州利比居民的免疫异常。利比受到闪石石棉的污染，这是1920年代初至1990年间蛭石开采和加工的结果。利比居民血清IG和自身抗体水平升高。总之，这些发现强烈表明，接触闪石石棉调节免疫功能。为了解决闪石石棉对免疫功能的影响，该提案侧重于CD 4 + T辅助细胞的活化和分化，这是产生免疫应答的关键事件。CD 4 + T细胞为B细胞提供细胞因子和接触依赖性帮助，促进免疫球蛋白分泌并允许同种型转换。特异性T细胞抗原受体（TCR）与APC上的同源MHC：肽配体的相互作用快速启动细胞内信号传导。我们和其他人已经表明，这种初始信号传导导致细胞质和膜结合蛋白大规模重新分布到T-APC相互作用的位点。这些分子在空间上和时间上被分离到称为超分子活化复合物的界面内的不同区域中。这些分子的积累和分离导致免疫突触（IS）的形成。IS是完全活化和分化为效应T细胞所必需的持续细胞内信号传导的位置。它也是CD 8 + T细胞释放溶细胞颗粒的位点和CD 4 + T细胞分泌效应细胞因子亚群的位置。免疫突触的分子成分可以对T细胞的活化状态具有显著影响。迄今为止，没有研究进行了系统的方法来检查闪石石棉的影响，在分子水平上的IS形成或T淋巴细胞活化。在这个建议中，我们将研究免疫突触的形成和特征的组成。