Neumann C M, Oughton J A, Kerkvliet N I
College of Veterinary Medicine, Oregon State University, Corvallis 97331.
Int J Immunopharmacol. 1993 May;15(4):543-50. doi: 10.1016/0192-0561(93)90069-b.
An in vivo model was used to examine the effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on various parameters of T-cell-activation. In this model, the hamster anti-mouse monoclonal antibody 145-2C11 (anti-CD3) to the CD3 portion of the murine T-cell receptor was injected into both rear footpads of female C57B1/6 mice and the draining popliteal and inguinal lymph node cells (LNC) were removed 24 h later. Cyclosporin A (CsA) was included as a known immunosuppressive control. As expected, CsA (50 mg/kg, i.p.) suppressed anti-CD3-induced proliferation, IL-2-driven 3H-TdR incorporation, and IL-2R expression. In contrast, TCDD unexpectedly enhanced anti-CD3-induced 3H-TdR incorporation. Flow cytometric analysis showed that TCDD treatment increased the percentage of both CD4+ and CD8+ cells cycling in S and G2M. LNC from TCDD-treated mice also had enhanced 3H-TdR incorporation when cultured in the presence of a saturating amount of exogenous mIL-2. TCDD did not significantly alter the percent positive or the number of IL-2 receptors (IL-2R) on either CD4+ or CD8+ cells when examined at several time points after anti-CD3 treatment. Both the kinetics and extent of anti-CD3-induced down-modulation of CD3 expression on CD4+ and CD8+ cells was unaffected by TCDD. TCDD alone did not result in enhanced 3H-TdR incorporation, cell cycling or IL-2R expression. Therefore, TCDD appears to be targeting T-cells that are undergoing activation rather than resting cells. The strength of the anti-CD3 model is evidenced by the fact that two known immunosuppressive compounds (CsA and TCDD) have distinct and opposite effects on T-cell activation. These findings suggest that the mechanism(s) by which CsA and TCDD impair T-cell function are different.
采用体内模型研究2,3,7,8-四氯二苯并对二恶英（TCDD）对T细胞激活的各种参数的影响。在该模型中，将针对小鼠T细胞受体CD3部分的仓鼠抗小鼠单克隆抗体145-2C11（抗CD3）注射到雌性C57B1/6小鼠的双侧后足垫中，24小时后取出引流的腘窝和腹股沟淋巴结细胞（LNC）。环孢素A（CsA）作为已知的免疫抑制对照。正如预期的那样，CsA（50mg/kg，腹腔注射）抑制抗CD3诱导的增殖、IL-2驱动的3H-TdR掺入以及IL-2R表达。相反，TCDD出人意料地增强了抗CD3诱导的3H-TdR掺入。流式细胞术分析表明，TCDD处理增加了处于S期和G2M期循环的CD4+和CD8+细胞的百分比。当在饱和量的外源性mIL-2存在下培养时，来自TCDD处理小鼠的LNC也具有增强的3H-TdR掺入。在抗CD3处理后的几个时间点检测时，TCDD对CD4+或CD8+细胞上IL-2受体（IL-2R）的阳性百分比或数量没有显著影响。抗CD3诱导的CD4+和CD8+细胞上CD3表达下调的动力学和程度均不受TCDD影响。单独的TCDD不会导致3H-TdR掺入、细胞周期或IL-2R表达增强。因此，TCDD似乎靶向正在经历激活的T细胞而非静止细胞。两种已知的免疫抑制化合物（CsA和TCDD）对T细胞激活具有不同且相反的作用，这一事实证明了抗CD3模型的有效性。这些发现表明，CsA和TCDD损害T细胞功能的机制不同。
