SUPPRESSION OF HUMORAL IMMUNITY BY BENZENE METABOLITES

这项研究的长期目标是基于对 通过自来水接触低水平苯的机制 居住在使用苯作为溶剂的工业附近的个人 调节体液免疫反应的抑制。尽管暴露于 工作场所中的高水平苯可能会导致 造血功能障碍和某些形式的肿瘤，本研究将重点放在 根据可能的免疫抑制能力的代谢产物 低浓度苯暴露后肝脏中的苯代谢 在很长一段时间内。提案的第一部分涉及 确定这些化合物对体液免疫的影响程度 系统。为此，正常的、静止的小鼠B细胞将被暴露 在体外对不同浓度的苯代谢物，单独或 在代谢产物的组合中，当被诱导增殖和 差异化。在一些实验中，这些细胞会被激活 多克隆的佛波酯和离子霉素，脂多糖， 抗免疫球蛋白加淋巴因子或经抗CD3治疗的固定T细胞 辅助性细胞和淋巴因子。将评估单元格的级别 在RNA和DNA合成中，进入不同阶段的细胞百分比 细胞周期，每个时间点存在的活细胞数，以及 一些生化信号的转导。此外，人口 暴露于苯代谢物的抗原特异性B细胞 在体外用特定抗原(胸腺非依赖性和 胸腺依赖)，以及在适当的情况下，照射的携带者特异性Th 细胞。代谢产物在诱导抗体合成中的作用 用多克隆刺激剂和特异性抗原进行检测。最后， 将研究淋巴因子介导的班级转换。这些实验 将定义苯代谢物干扰的水平 发展体液反应。在提案的第二部分，MICS将 接触饮用水中的苯的时间长达12个月。在… 在不同的时间，动物将被牺牲，并从两者中恢复B细胞 脾和肠系膜淋巴结功能的体外评价 如上所述。这些实验将确定是否不同 次级淋巴隔室更容易受到苯的影响 从肝脏释放的代谢物。此外，细胞暴露在太多的 对代谢物的较长时间段的研究可以采用类似的方法 细胞在体外短期暴露。

The long-term objectives of this study center upon understanding the mechanisms by which exposure to low levels of benzene via the water supply of individuals residing close to industries using benzene as a solvent mediates the suppression of humoral immune responses. Although exposure to high levels of benzene in the workplace can result in the development of hematopoietic dyscrasias and certain forms of tumors, this study will focus upon possible immunosuppressive capabilities of the metabolic products of benzene metabolism in the liver following exposure to low levels of benzene over an extended period of time. The first part of the proposal deals with defining the levels at which these compounds impact with the humoral immune system. For this purpose, normal, resting, murine B cells will be exposed in vitro to varying concentrations of benzene metabolites, either singly or in combinations of metabolites, while being induced to proliferate and differentiate. In some experiments, the cells will be activated polyclonally by phorbol ester and ionomycin, by lipopolysaccharide, by anti-immunoglobulin plus lymphokines, or by anti-CD3 treated, fixed T helper (TH) cells plus lymphokines. The cells will be evaluated for levels of RNA and DNA synthesis, percent cells entering the various stages of the cell cycle, number of viable cells present at each time point, and for the transduction of a number of biochemical signals. In addition, populations of antigen-specific B cells exposed to benzene metabolites will be challenged in vitro with specific antigen (both thymus-independent and thymus-dependent) and when appropriate, irradiated, carrier-specific Th cells. The effect of the metabolites upon induction of antibody synthesis by polyclonal stimulants and specific antigen will be assessed. Finally, lymphokine-mediated class switching will be studied. These experiments will define the levels at which the benzene metabolites interfere with the developing humoral response. In the second part of the proposal, mice will be exposed to benzene in their drinking water for up to 12 months. At various times, animals will be sacrificed and B cells recovered from both the spleen and mesenteric lymph nodes for in vitro evaluation of function as described above. These experiments will determine if different secondary lymphoid compartments are more susceptible to the benzene metabolites released from the liver. In addition, cells exposed for much longer periods of time to the metabolites can be studies in similar ways as cells exposed short-term vitro.