Application of tumor, bacterial and parasite susceptibility assays to study immune alterations induced by environmental chemicals
Application of tumor, bacterial and parasite susceptibility assays to study immune alterations induced by environmental chemicals
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应用肿瘤、细菌和寄生虫敏感性测定来研究环境化学物质引起的免疫改变
DOI：
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发表时间：
1982
影响因子：
10.4
通讯作者：
L. Lauer
中科院分区：
文献类型：
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作者：
J. Dean;M. Luster;G. Boorman;R. W. Leubke;L. Lauer
描述和评价了研究环境化学品对细菌和寄生虫病以及可移植肿瘤细胞的免疫监视和破坏的影响的模型系统。在成年或出生前/出生后暴露于几种原型化学品的雌性B6 C3 F1小鼠中进行了研究。所使用的原型化学物质包括合成雌激素己烯雌酚（DES）、多环芳烃苯并（a）芘（B[a]P）和致癌促进剂12-0-十四烷酰基-佛波醇-13-0-乙酸酯（TPA）。采用的宿主抗性模型主要依赖于功能性胸腺依赖性免疫，尽管体液免疫被认为在寄生虫模型中也有作用。这些模型包括：用一定剂量PYB 6肿瘤细胞皮下攻击，导致10-20%肿瘤发生率（TD 10 -20）;用B16黑素瘤细胞静脉内攻击;用一定剂量的单核细胞增多性李斯特菌攻击，导致10-20%死亡率（LD 10 -20）;用一定剂量的E.大肠杆菌脂多糖内毒素导致10-20%的致死率（LD 10 -20）;以及用旋毛虫幼虫攻击以进行寄生虫排出动力学研究。在DES暴露的小鼠中观察到单核细胞增生李斯特菌攻击后死亡率增加。B（a）P和TPA暴露没有改变宿主对该微生物的抗性。DES后观察到的死亡率增加与第4天脾脏和肝脏中活李斯特菌数量的显著增加相关，此时T细胞免疫被认为是表达的，但细菌计数与第1天的对照小鼠相似，此时MΦ被认为发挥其最大作用。这些数据表明，DES暴露后发现的李斯特菌易感性增加可能是由于T细胞缺陷，尽管DES处理的M β的细胞内杀伤能力尚未得到很好的研究。用5 × 103个活的同基因PYB 6肿瘤细胞攻击后的肿瘤敏感性研究显示，未处理的成年B6 C3 F1小鼠抵抗肿瘤形成，肿瘤形成的发生率仅为10-20%。相比之下，成年时暴露于DES或TPA的小鼠在TPA后的肿瘤发生率为70-100%，暴露于DES后的肿瘤发生率高达90%。在所有病例中，肿瘤都是进行性的，并导致死亡。在该模型中，B（a）P未改变对照组的肿瘤发生率。使用B16黑色素瘤静脉内激发模型和125 IUdR定量肿瘤质量的初步数据显示，该模型对非特异性激活的巨噬细胞杀伤敏感。用活化的巨噬细胞处理的DES小鼠没有表现出肿瘤质量增加，而暴露于TPA或强效免疫抑制剂环磷酰胺的小鼠在其肺部的肿瘤质量显著增加。旋毛虫成虫从肠道排出显然也需要功能性T细胞和可能的体液免疫的一些元素。暴露于DES和B（a）P的小鼠在第14天表现出肠道中蠕虫数量增加。DES或B（a）P暴露后，对革兰氏阴性内毒素（LPS）的敏感性明显增加。这些数据表明，LPS的解毒与完整的M β细胞群有关。本文提供的数据证明了拟用于检测免疫改变的宿主耐药性试验组的灵敏度。T细胞功能的改变似乎与对细菌和肿瘤细胞攻击的敏感性增加相关。
Model systems to study the effects of chemicals of environmental concern on bacterial and parasitic diseases as well as the immunosurveillance and destruction of transplantable tumor cells were described and evaluated. Studies were conducted in female B6C3F1 mice following adult or pre/postnatal exposure to several prototype chemicals. The prototype chemicals employed included the synthetic estrogen diethylstilbestrol (DES), the polycyclic aromatic hydrocarbon benzo(a)pyrene (B[a]P), and the carcinogenesis promoting agent 12-0-tetradecanoyl-phorbol-13-0-acetate (TPA). The host resistance models employed depend primarily on functional thymus-dependent immunity, although humoral immunity is suggested to have a role in the parasite model as well. These models include: subcutaneous challenge with a dose of PYB6 tumor cell causing a 10-20% incidence (TD10–20) of tumor; intravenous challenge with B16 melanoma cells; challenge with a dose of Listeria monocytogenes causing a 10-20% incidence of mortality (LD10–20); challenge with a dose of E. coli lipopolysaccharide endotoxin causing a 10-20% incidence of lethality (LD10–20); and challenge with larvae of Trichinella spiralis for parasite expulsion kinetic studies. Increased mortality was observed following Listeria monocytogenes challenge in DES-exposed mice. B(a)P and TPA exposure did not alter host resistance to this organism. The increased mortality observed following DES was associated with a significant increase in the number of viable Listeria in the spleens and livers at 4 days, a time when T-cell immunity is thought to be expressed, but bacterial counts were similar to control mice at day 1, a time when MΦ are thought to exert their greatest effect. These data suggest that the increased Listeria susceptibility found following DES exposure may result from a T-cell defect, although the intracellular killing capacity of DES-treated Mϕ's has not been well examined. Tumor susceptibility studies following challenge with 5 × 103 viable syngeneic PYB6 tumor cells revealed that nontreated adult B6C3F1 mice resisted tumor formation, with only a 10-20% incidence of tumor formation. In contrast, mice exposed to DES or TPA as adults had a tumor frequency of from 70-100% following TPA and up to 90% following DES exposure. In all cases the tumors were progressive and resulted in death. B(a)P did not alter the frequency of tumor incidence from controls in this model. Preliminary data, using the B16 melanoma intravenous challenge model and 125IUdR to quantitate tumor mass revealed this model was sensitive to non-specifically activated macrophage kill. DES treated mice with activated macrophages did not demonstrate increased tumor mass, while mice exposed to TPA or the potent immunosuppressive agent cyclophosphamide had a significantly increased tumor mass in their lungs. Expulsion of Trichinella spiralis adults from the gut also apparently required functional T-cells and possibly some element of humoral immunity. Mice exposed to DES and B(a)P exhibited increased numbers of adult worms in the gut at day 14. Sensitivity to gram-negative endotoxin (LPS) was apparently increased following exposure to DES or B(a)P. These data suggest that the detoxification of LPS is related to an intact Mϕ population. The data presented here demonstrate the sensitivity of the host resistance assay panel proposed for detecting immune alteration. Alteration of T-cell function appeared to correlate with increased susceptibility to bacterial and tumor cell challenge.