Expression of Cytokines and Immunoglobulins in Toxicant-Exposed Human Lymphocytes

尽管有重要证据表明 2，3，7，8-四氯二苯二恶英(TCDD)改变淋巴细胞 在小鼠身上的功能，很少有研究能检测到 TCDD对人淋巴细胞的影响虽然已经有了 一些不经意间接触到TCDD的人，通过工业 事故或环境污染，目前还没有 在暴露的个体中观察到一致的免疫缺陷。 对德国化学工人的研究证明了这种变化 淋巴细胞亚群和功能参数20年 在接触TCDD后。作为继续努力评估 环境接触TCDD对健康的影响势在必行 我们检查可能敏感的终结点 人类暴露的预测因素并将这些生物标志物相互关联 结合血液中TCDD水平，确定对电位的影响 混杂变量对生物标记物表达的影响 以及个体内部的差异。确定其他 生物标志物可帮助识别个人或群体 接触空气后罹患疾病或肿瘤的风险更大 二恶英和相关化合物。外周血样本 淋巴细胞取自几组对照或 接触TCDD的个人。这些样本是 在培养中单独或在TCDD存在的情况下刺激有丝分裂原， 72小时后收获细胞和培养上清。到目前为止 我们检查了一组工人的上清液，这些工人 受雇于德国汉堡-摩尔法尔的一家化工厂 1951年至1984年由勃林格-英格尔海姆公司运营，生产了 有机氯除草剂和杀虫剂(包括 2，4，5-三氯苯氧基乙酸)和阿片类药物。TCDD 该工厂的污染在1984年得到证实，并严重 在一组工人中观察到死亡率的增加 从1952年到1984年，在这家工厂工作了至少3个月。 外周血淋巴细胞分离和血清二恶英分析 是在1992年从110人的队列中获得的， 与美因茨大学(底特律)的临床医生合作 Jung和Johannes Konietzko)和德国 癌症研究中心。TCDD的体外治疗导致了 有丝分裂原刺激的T细胞的产生显著减少 辅助性1型(TH1)细胞因子IL-2和干扰素 这一队列中的淋巴细胞培养中存在γ-干扰素(IFNγ)。我们 相信TH1细胞因子的变化是体外实验的结果 暴露，因为与标准生物标志物的相关性有限 TCDD暴露，如TCDD血浆总水平或总血浆 TEQ。相反，似乎存在与剂量相关的相关性 个体TCDD的身体负担和分泌减少之间的关系 辅助性T细胞2型细胞因子白介素4的相关性 也可以在体外TCDD诱导的 乙氧基间苯二酚-O-脱乙基酶活性与肿瘤分泌物 肿瘤坏死因子α。虽然看起来可能有一些 对免疫球蛋白(Ig)分泌有显著影响，尤其是对 IgA和IgG2，个体间变异性相当高，并且 将需要复杂的统计分析来梳理出 曝光特定的效果。与约瑟夫博士合作 哈斯曼，数据集正在进行多变量分析，以检查 体内外免疫效应的相关性研究 暴露的生物标志物，并确定 令人困惑的变量，如性别、吸烟状况等。

Although there is significant evidence that 2,3,7,8-tetrachlorodibenzodioxin (TCDD) alters lymphocyte function in mice, there have been very few studies which examine the effects of TCDD on human lymphocytes. While there have been a number of inadvertent exposures to TCDD, via industrial accidents or environmental contamination, there have been no consistent immunological defects observed in exposed individuals. Studies in German chemical workers have demonstrated alterations in lymphocytes subpopulations and functional parameters 20 years after exposure to TCDD. As part of a continued effort to assess the health effects of environmental exposures to TCDD it is imperative that we examine endpoints which have the potential to be sensitive predictors of human exposure and to correlate these biomarkers with blood TCDD levels, determine influence of potential confounding variables on biomarker expression, and evaluate inter- and intra-individual variation. Identification of additional biomarkers may aid in identifying individuals or populations at greater risk of developing disease or neoplasia after exposure to dioxins and related compounds. Samples of peripheral blood lymphocytes were obtained from several cohorts of control or TCDD-exposed individuals. These samples were mitogen-stimulated in culture, alone or in the presence of TCDD, and the cells and culture supernatants harvested after 72 hr. To date we have examined supernatants from a group of workers who were employed at a chemical plant in Hamburg-Moorfleet, Germany operated by Boehringer-Ingelheim from 1951-1984 that produced organochlorine herbicides and pesticides (including 2,4,5-trichlorophenoxyacetic acid) and opioids. TCDD contamination at this plant was confirmed in 1984 and significant increases in mortality have been observed in a cohort of workers employed at this plant for at least 3 months from 1952-1984. Peripheral blood for lymphocyte isolation and serum dioxin analysis was obtained from a cohort of 110 individuals in 1992, in collaboration with clinicians at the University of Mainz (Detlev Jung and Johannes Konietzko) and a biostatistician at the German cancer Research center. In vitro treatment with TCDD resulted in a significant decreases in the mitogen-stimulated production of the T Helper 1 type (TH1) cytokines Interleukin 2 (IL2) and Interferon gamma (IFNgamma) in ymphocyte cultures from this cohort. We believe the alterations TH1 cytokines are a result of the in vitro exposure as there is limited correlation with standard biomarkers of TCDD exposure such as total TCDD plasma levels or total plasma TEQ. In contrast, there appears to be a dose-related correlation between individual TCDD body burden and decreased secretion of the T Helper 2 type cytokine Interleukin 4. Significant correlations were also seen between in vitro TCDD-inducible ethoxyresorufin-O-deethylase activity and secretion of tumor necrosis factor alpha. While it appears that there may be some significant effects on immunoglobulin (Ig) secretion, particularly for IgA and IgG2, interindividual variability is quite high, and sophisticated statistical analyses will be required to tease out exposure-specific effects. In collaboration with Dr. Joseph Haseman, the dataset is undergoing multivariate analysis to examine correlations between immunologic effects and in vivo and in vitro biomarkers of exposure, and to determine the effects of confounding variables such as gender, smoking status, etc.