MECHANISM OF METAL MEDIATED IMMUNOSUPPRESSION

金属介导的免疫抑制机制

• 批准号: 2701322
• 负责人: MICHAEL A LYNES
• 金额: $ 14.81万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-05-01 至 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2701322
• 关键词: B lymphocyte; T lymphocyte; cell differentiation; cell line; cytokine; environmental toxicology; enzyme induction /repression; heavy metals; helper T lymphocyte; humoral immunity; hybridomas; immune tolerance /unresponsiveness; laboratory mouse; laboratory rabbit; macrophage; metallothionein; monoclonal antibody

DESCRIPTION: (Adapted from the Investigator's Abstract) Heavy metals (such as Cd, Hg, Ni, Zn, Cu, and Pb) are increasingly important contaminants of air, water, and soils. One of the critical biological systems which can be altered by exposure to heavy metals is the immune system, where inappropriate changes in immune capacity can result in immunodeficiency or autoimmune disease. While there is a great deal of interest in the mechanisms by which heavy metals alter immunity, there remain many unresolved issues. In preliminary studies, the investigators have examined the contributions that MT (a small, cysteine-rich metalloprotein that is rapidly induced in cells following heavy metal exposure) might make to altered immune activity. Metallothionein may be responsible for some of the forms of humoral immunosuppression associated with metal exposure. For example, the investigators have found that MT suppresses specific T-dependent humoral responses, and that some aspects of macrophage function are altered by MT. They have also found that monoclonal antibodies to MT developed in our laboratory can block some in vivo immunomodulatory activities of MT. The investigator's findings suggest that MT induced by heavy metal exposure (or indeed by exposure to other toxicants) is responsible for decreases in immunity as a consequence of antigen-presenting cell/helper T-cell interactions. The central parameters of the humoral response that are potential targets of the suppressive effect of MT will be evaluated. These experiments will establish the mechanisms by which suppressive effects occur. The Specific Aims are to: (1) explore the dynamics of in vivo MT interactions with the immune system and to determine if suppression of humoral immunity is found in both T-dependent and -independent responses, (2) to examine the effects of MT on the role that T-lymphocytes play in regulation of the humoral immune response, (3) to determine whether the interactions of helper T-cells and macrophages are altered by MT, and (4) to establish whether patterns of B-cell differentiation are altered by the presence of MT. This research will have important implications both for the identification of individuals at particular risk for immune disease as a consequence of heavy metal exposure, and for the diagnosis and treatment of individuals exposed to excessive levels of these important environmental toxins.

描述：（根据研究者的摘要进行了改编）重金属（这样 作为CD，HG，Ni，Zn，Cu和Pb）是越来越重要的污染物 空气，水和土壤。 可以是关键的生物系统之一 通过暴露于重金属的改变是免疫系统，其中 免疫能力的不当变化可能导致免疫缺陷或 自身免疫性疾病。 虽然对 重金属改变免疫力的机制，仍然存在许多 未解决的问题。 在初步研究中，研究人员研究了贡献 那个MT（一种小的，富含半胱氨酸的金属蛋白，迅速诱导 重金属暴露后的细胞可能会导致免疫活性改变。 金属硫蛋白可能是某些形式的体液造成的 与金属暴露有关的免疫抑制。 例如， 研究人员发现MT抑制特定的T依赖性体液 响应和巨噬细胞功能的某些方面被MT改变了。 他们还发现，我们在我们的MT中开发的单克隆抗体 实验室可以阻止一些MT的体内免疫调节活动。 这 研究者的发现表明，由重金属暴露引起的MT（或 实际上，通过接触其他有毒物质）负责减少 由于抗原呈递细胞/助手T细胞的免疫力 互动。 体液响应的中心参数是 将评估MT抑制作用的潜在靶标。 这些 实验将建立抑制作用的机制 发生。 具体目的是：（1）探索体内MT的动态 与免疫系统的相互作用，并确定是否抑制 在T依赖性和非依赖性反应中都发现了体液免疫力， （2）检查MT对T淋巴细胞中作用的影响 调节体液免疫反应，（3）确定是否是否 辅助T细胞和巨噬细胞的相互作用通过MT改变，（4）至 确定B细胞分化模式是否通过 MT的存在。 这项研究将对识别具有重要意义 由于 重金属暴露，以诊断和治疗个体 暴露于这些重要的环境毒素的过度水平。