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《调查者摘要》)重金属(如 作为镉、汞、镍、锌、铜和铅)是日益重要的污染物 空气、水和土壤。关键的生物系统之一，可以是 因接触重金属而改变的是免疫系统，其中 免疫能力的不适当变化可导致免疫缺陷或 自身免疫性疾病。虽然有很大的兴趣在 重金属改变免疫力的机制仍然有许多 未解决的问题。 在初步研究中，调查人员检查了这些贡献 MT(一种小的，富含半胱氨酸的金属蛋白，在 重金属暴露后的细胞)可能会导致免疫活性改变。 金属硫蛋白可能与某些形式的体液有关 与金属接触相关的免疫抑制。例如， 研究人员发现，MT抑制特定的T依赖体液 MT改变了巨噬细胞功能的某些方面。 他们还发现，抗MT的单抗在我们的 实验室可阻断MT的部分体内免疫调节活性。这个 研究人员的发现表明，重金属暴露(或 确实是因为接触了其他毒物)导致了 抗原提呈细胞/辅助性T细胞引起的免疫 互动。体液反应的中心参数是 MT抑制作用的潜在靶点将被评估。这些 实验将建立起抑制作用的机制 发生。具体目的是：(1)探索体内MT的动力学 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依赖反应和非T依赖反应中， (2)检测MT对T淋巴细胞功能的影响。 体液免疫反应的调节，(3)确定 MT改变辅助性T细胞和巨噬细胞的相互作用，(4) 确定B细胞分化模式是否被 MT的存在。 这项研究将对两种身份的识别具有重要的意义 因以下原因而特别容易患免疫性疾病的人 重金属暴露，以及个人的诊断和治疗 暴露在过量的这些重要的环境毒素中。