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：（改编自研究者摘要）重金属（例如 （如镉、汞、镍、锌、铜和铅）是越来越重要的污染物 空气、水和土壤。 重要的生物系统之一 因接触重金属而改变的是免疫系统，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。 虽然人们对此抱有很大兴趣 重金属改变免疫力的机制仍有许多 未解决的问题。 在初步研究中，研究人员检查了贡献 MT（一种富含半胱氨酸的小金属蛋白，在 重金属暴露后的细胞）可能会改变免疫活性。 金属硫蛋白可能与某些体液形式有关 与金属接触有关的免疫抑制。 例如， 研究人员发现 MT 抑制特定的 T 依赖性体液 反应，并且巨噬细胞功能的某些方面会被 MT 改变。 他们还发现，我们的研究人员开发了针对 MT 的单克隆抗体。 实验室可以阻断MT的一些体内免疫调节活性。 这 研究人员的研究结果表明，重金属暴露（或 实际上是通过接触其他有毒物质）导致 抗原呈递细胞/辅助 T 细胞产生的免疫力 互动。 体液反应的核心参数是 将评估 MT 抑制作用的潜在目标。 这些 实验将建立抑制作用的机制 发生。 具体目标是：（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 体液免疫存在于 T 依赖性和非依赖性反应中， (2) 考察MT对T淋巴细胞的作用的影响 体液免疫反应的调节，（3）确定是否 辅助 T 细胞和巨噬细胞的相互作用被 MT 改变，并且 (4) 确定 B 细胞分化模式是否因 MT 的存在。 这项研究对于鉴定具有重要意义 由于以下原因而面临免疫疾病特殊风险的个体 重金属暴露，以及用于个人的诊断和治疗 暴露于过量的这些重要环境毒素中。