Prell R A, Oughton J A, Kerkvliet N I
Department of Agricultural Chemistry, Oregon State University, Corvallis 97331, USA.
Int J Immunopharmacol. 1995 Nov;17(11):951-61. doi: 10.1016/0192-0561(95)00080-1.
The influence of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure on the cytokine-dependent toxicity syndrome induced by the injection of 145-2C11 (anti-CD3), a hamster monoclonal antibody to the CD3 epsilon portion of the murine T-cell receptor, was studied. This syndrome has been attributed to the transient release of several cytokines including TNF-alpha, IFN-gamma, IL-2, IL-3, IL-6, and GM-CSF. Exposure of C57Bl/6 mice to TCDD (15 micrograms/kg) 2 days prior to anti-CD3 injection exacerbated anti-CD3-induced toxicity as evidenced by significantly enhanced and prolonged body weight loss and lymphoid tissue atrophy. Unexpectedly, TCDD exposure did not alter plasma levels of TNF or IL-2 at any time after anti-CD3 injection. However, plasma IFN-gamma was significantly reduced at 24 h and plasma IL-6 levels were elevated 48 h after anti-CD3 injection in TCDD-treated mice. In addition, TCDD exposure resulted in elevated levels of plasma GM-CSF at 24 and 48 h. Since the body weight of TCDD-treated mice diverged from vehicle-treated mice at 48 h, it suggests that the increased IL-6 and GM-CSF may have contributed to the prolonged loss of body weight. The ability of spleen cells from vehicle- and TCDD-treated mice to produce cytokines was evaluated in vitro at various times after anti-CD3 injection. TCDD treatment resulted in reduced IL-2 and GM-CSF production at 90 min but increased GM-CSF production at 48 h post-anti-CD3 injection. In contrast, TCDD exposure did not influence cytokine production by spleen cells from mice injected with a control IgG and activated in vitro with anti-CD3. Flow cytometric analysis showed that the percentage of CD4+ cells in the draining lymph nodes from TCDD-treated mice was reduced 48-144 h post-anti-CD3 injection. In contrast, the percentage of CD8+ cells was not affected by TCDD exposure. A high fraction of lymph node cells (LNC) from TCDD-treated animals showed decreased forward angle light scatter and increased 90 degrees light scatter following anti-CD3 injection, which is a pattern characteristic of cells undergoing apoptosis. In contrast, few LNC from vehicle-treated animals showed this light scatter profile. These data suggest that TCDD may be targeting T-helper cells during activation resulting in activation-driven cell death (apoptosis) rather than differentiation.
研究了2,3,7,8-四氯二苯并-对-二噁英（TCDD）暴露对注射145-2C11（抗CD3）诱导的细胞因子依赖性毒性综合征的影响，145-2C11是一种针对小鼠T细胞受体CD3ε部分的仓鼠单克隆抗体。这种综合征归因于包括TNF-α、IFN-γ、IL-2、IL-3、IL-6和GM-CSF在内的多种细胞因子的短暂释放。在注射抗CD3前两天，将C57Bl/6小鼠暴露于TCDD（15微克/千克）会加剧抗CD3诱导的毒性，体重显著增加和延长的体重减轻以及淋巴组织萎缩证明了这一点。出乎意料的是，TCDD暴露在抗CD3注射后的任何时间都没有改变血浆中TNF或IL-2的水平。然而，在TCDD处理的小鼠中，抗CD3注射后24小时血浆IFN-γ显著降低，48小时血浆IL-6水平升高。此外，TCDD暴露导致24小时和48小时血浆GM-CSF水平升高。由于TCDD处理的小鼠体重在48小时时与载体处理的小鼠不同，这表明IL-6和GM-CSF的增加可能导致了体重的长期减轻。在抗CD3注射后的不同时间，体外评估了载体处理和TCDD处理小鼠的脾细胞产生细胞因子的能力。TCDD处理导致抗CD3注射后90分钟IL-2和GM-CSF产生减少，但48小时GM-CSF产生增加。相反，TCDD暴露不影响注射对照IgG并在体外用抗CD3激活的小鼠脾细胞产生细胞因子。流式细胞术分析表明，抗CD3注射后48-144小时，TCDD处理小鼠引流淋巴结中CD4+细胞的百分比降低。相反，CD8+细胞的百分比不受TCDD暴露的影响。抗CD3注射后，TCDD处理动物的大部分淋巴结细胞（LNC）显示前向角光散射降低，90度光散射增加，这是细胞凋亡的特征模式。相反，载体处理动物的LNC很少显示这种光散射特征。这些数据表明，TCDD可能在激活过程中靶向辅助性T细胞，导致激活驱动的细胞死亡（凋亡）而不是分化。
