SUPPRESSION OF HUMORAL IMMUNITY BY BENZENE METABOLITES

本研究的长期目标是了解 通过供水暴露于低水平苯的机制 居住在使用苯作为溶剂的工业附近的个人 介导体液免疫应答的抑制。 虽然暴露于 工作场所的高浓度苯会导致 造血恶液质和某些形式的肿瘤，这项研究将重点 在可能的免疫抑制能力的代谢产物， 低浓度苯暴露对肝脏苯代谢的影响 在很长一段时间内。 建议的第一部分涉及 定义这些化合物对体液免疫影响的水平 系统 为此，将暴露正常的静息鼠B细胞 在体外不同浓度的苯代谢物，无论是单独或 在代谢物的组合中，同时被诱导增殖， 区分。 在某些实验中，细胞会被激活 佛波酯和离子霉素，脂多糖， 抗免疫球蛋白加淋巴因子，或通过抗CD3处理的固定T 辅助（TH）细胞加淋巴因子。 将对细胞进行水平评估 RNA和DNA合成的百分比，细胞进入不同阶段的百分比， 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细胞将 在体外用特异性抗原（胸腺非依赖性和 胸腺依赖性），适当时，照射，载体特异性Th 细胞 代谢产物对诱导抗体合成的影响 通过多克隆刺激剂和特异性抗原进行评估。 最后， 将研究淋巴因子介导的类别转换。 这些实验 将定义苯代谢物干扰 产生体液反应 在提案的第二部分，老鼠将 在饮用水中接触苯长达12个月。 在 在不同的时间，处死动物，并从两个组织中回收B细胞。 脾和肠系膜淋巴结用于体外功能评价 如上面所描述的那样。 这些实验将确定是否不同 次级淋巴区室对苯更敏感 从肝脏释放的代谢物。 此外，细胞暴露于 更长时间的代谢产物可以用类似的方法进行研究， 细胞短期暴露于体外。

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.