Blot C, Lebrec H, Roger R, Bohuon R, Pallardy M
Laboratoire de Toxicologie, INSERM CJF 93-01, Faculté de Pharmacie Paris XI, Châtenay-Malabry, France.
Toxicology. 1994 Nov-Dec;94(1-3):231-45. doi: 10.1016/0300-483x(94)90041-8.
Knowledge of interspecies differences, commonly evaluated in other disciplines such as carcinogenesis, is a prerequisite for an appropriate assessment of immunotoxicological risks. The purpose of this study was to assess interspecies differences following exposure of Fischer 344 rats and B6C3F1 mice to cyclosporine A. These animals were exposed daily to cyclosporine A by oral gavage at 0, 5, 10, 25 mg/kg/day for 14 consecutive days. The results showed that splenocytes lymphoproliferation in response to concanavalin A or phytohemagglutinin, and IgM antibody-forming cells to sheep red blood cells, were affected in both species. Cytotoxic T-lymphocyte activity and mixed lymphocyte response were significantly inhibited in the rat following cyclosporine A exposure while they remained unaffected in the mouse. In contrast, natural killer cell activity was significantly depressed in the B6C3F1 mouse but not in the Fischer 344 rat. The discrepancies between the two species in cytotoxic T-lymphocyte activity and mixed lymphocyte response assays could partially be explained by the constantly higher blood level of cyclosporine A in the rat than in the mouse. When these tests were performed using rat and mouse splenocytes exposed to cyclosporin A in vitro (10(-9) to 10(-5) M) it was possible to correlate in vivo and in vitro data for concanavalin A- and phytohemagglutinin-induced lymphoproliferation and for cytotoxic T-lymphocyte activity but not for mixed lymphocyte response. Natural killer activity was 10-fold more sensitive in mice than in rats in vitro but these results did not clarify the in vivo difference. In conclusion, these results emphasize that the utilization of more than one species should be considered when assessing immunotoxicity.
了解种间差异是恰当评估免疫毒理学风险的前提条件，这种差异在诸如致癌作用等其他学科中通常会进行评估。本研究的目的是评估Fischer 344大鼠和B6C3F1小鼠暴露于环孢素A后的种间差异。这些动物连续14天每天通过灌胃给予环孢素A，剂量分别为0、5、10、25 mg/kg/天。结果表明，两种动物对刀豆球蛋白A或植物血凝素的脾细胞淋巴细胞增殖反应，以及对绵羊红细胞的IgM抗体形成细胞均受到影响。环孢素A暴露后，大鼠的细胞毒性T淋巴细胞活性和混合淋巴细胞反应受到显著抑制，而小鼠则未受影响。相反，B6C3F1小鼠的自然杀伤细胞活性显著降低，而Fischer 344大鼠则未受影响。大鼠和小鼠在细胞毒性T淋巴细胞活性和混合淋巴细胞反应试验中的差异，部分原因可能是大鼠体内环孢素A的血药浓度持续高于小鼠。当使用体外暴露于环孢素A（10^(-9)至10^(-5) M）的大鼠和小鼠脾细胞进行这些试验时，刀豆球蛋白A和植物血凝素诱导的淋巴细胞增殖以及细胞毒性T淋巴细胞活性的体内和体外数据具有相关性，但混合淋巴细胞反应的数据不具有相关性。体外实验中，小鼠的自然杀伤活性比大鼠敏感10倍，但这些结果并未阐明体内差异。总之，这些结果强调在评估免疫毒性时应考虑使用多种物种。
