Immunotoxic effects of lead on cytokine expression

描述（由申请人提供）：铅（Pb）改变 免疫反应是多因素的，MHC和非MHC基因都可能 参与，因为似乎对T细胞、B细胞有独立的影响 和巨噬细胞，这些影响似乎涉及不同的细胞因子， 信号/转录因子。该项目的长期目标是 确定铅改变淋巴细胞发育的亚细胞机制 （对记忆细胞幼稚）和记忆T细胞的活化和反应性 这可能会影响免疫力，导致低或高反应性。这 一项提案验证了重金属铅可以改变免疫状态的假设 通过生物化学和分子调节， 2型反应的发展环境，并取决于 一种特殊类型的免疫反应，需要防御感染性疾病， 代理，癌症或自我反应反应的调节，这种“偏斜”可能 与I型免疫减弱和II型免疫增强相关的病理学增加 应答化学、物理和/或情绪压力之间的协同作用可以 增强免疫反应性向1型或2型反应的倾斜; 短期的不平衡需要适当的防御，但长期的不平衡需要适当的防御。 不平衡加剧了病症。因此，诸如Pb的环境剂可以 改变平衡足以增加发病率。突变体（基因过表达 或缺陷）H-2d小鼠将被用来评估特定的 基因的“歪斜”现象。需要解决的具体问题是： 铅改变IFN？巨噬细胞的反应性，如 IL 10、IL 12或IL 18的产生被改变，并且无论细胞巯基 是否可以用T细胞实现Pb“偏斜” 仅特异于OVA或是否具有自身反应性的T细胞（或金属相关的 无论是B细胞还是特定类型的T细胞， 子集（例如，NK样T细胞）是必需的， 环境; IL-4反应性涉及哪些分子机制 T细胞;什么细胞负责2型环境诱导 的Pb。将通过流式细胞术和免疫荧光法测定细胞类型 显微镜细胞因子和信号传导因子的存在将通过 ELISA、微阵列分析（或RNA酶保护）和Western分析。铅头 美国毒物与疾病登记署有毒物质清单及其诱发或改变 与免疫反应相关的疾病的发病率需要更好地 明白这种细胞和分子的方法应该确定的机制， 铅具有免疫调节作用，有助于评价铅的健康危害， 暴露风险的分子基础。

DESCRIPTION (provided by applicant): The mechanisms by which lead (Pb) alters immune reactivities are multifactorial, both MHC and non-MHC genes are likely involved, in that there appear to be independent effects on T cells, B cells and macrophages, and these effects appear to involve different cytokines and signaling/transcription factors. The long-term goal of this project is to determine the sub cellular mechanisms by which Pb alters lymphocyte development (naive to memory cells) and the activation and reactivity of memory T cells which could influence immunity causing hypo- or hyper-responsiveness. This proposal tests the hypothesis that the heavy metal Pb can alter immune status by biochemical and molecular modulations resulting in a preferential environment for development of type-2 responses, and dependent on the particular type of immune response needed for defense against an infectious agent, cancer or regulation of self-reactive response, this "skewing" may increase pathologies associated with lessened type-] and enhanced lype-2 immune responses. Synergies between chemical, physical and/or emotional stresses can enhance the skewing of immune reactivities toward type-] or type-2 responses; short-term imbalance is needed for appropriate defenses, but long-term imbalance exacerbates pathologies. Thus, an environmental agent such as Pb may alter the balance enough to increase morbidity. Mutant (genetic over-expressing or deficient) H-2d mice will be employed to assess the involvement of specific genes in the "skewing" phenomenon. Specific questions to be addressed are: how Pb alters kinetic production of IFN?gamma; how macrophage reactivities, such as production of ILl 0, ILl 2 or ILl 8, are altered, and whether cellular thiol modifications are involved; whether Pb "skewing" can be achieved with T cells specific only to OVA or whether T cells with self-reactivity (or metal-related specificities) are needed, whether B cells or a particular type of T cell subset (e.g., NK-like T cells) are required and within what particular cytokine environment; what molecular mechanisms are involved with the IL-4 reactivities of T cells; and what cells are responsible for the type-2 environment induced by Pb. Cell types will be assayed by flow cytometry and immunofluorescence microscopy. The presence of cytokines and signaling factors will be assessed by ELISA, microarray analysis (or RNAse protection) and western analyses. Pb heads the ATSDR list of toxic substances and its potential to induce or modify incidence of diseases associated with immune reactivities needs to be better understood. This cellular and molecular approach should identify the mechanisms by which Pb is immunomodulatory and assist evaluation of its health hazard and the molecular basis for the risks in exposure.