Roman D, Ulrich P, Paul G, Court M, Vit P, Kehren J, Mahl A
Novartis Pharma AG, Preclinical Safety, Basel, Switzerland.
Toxicol Lett. 2004 Apr 1;149(1-3):133-40. doi: 10.1016/j.toxlet.2003.12.027.
The calcineurin inhibitors cyclosporin A (CsA), tacrolimus (FK506) and pimecrolimus (ASM981) are on the market for the oral treatment of psoriasis and atopic dermatitis and topical treatment of atopic dermatitis, respectively. The effect of these treatments on the immune response was investigated in this study after immunisation of rats with keyhole limpet hemocyanin (KLH). Male rats (10 per group) were orally administered pimecrolimus at 10 or 30 mg/kg/day), tacrolimus at 3 mg/kg/day or CsA at 20 mg/kg/day for 4 weeks. Control animals similarly received the vehicle only. The last five animals per group were immunised and challenged with KLH on days 16 and 24, respectively. Eight days after the last injection, the immune function was investigated by detecting KLH-specific antibodies in the serum and by examination of cell infiltration at the site of the KLH-challenge. In addition, a correlation between functional and structural changes was established by quantification of lymphocyte sub-populations in the blood or residing in lymphatic tissue. In KLH-immunised rats, CsA caused complete suppression of the KLH-specific IgM and IgG production, whereas only IgG production was affected by pimecrolimus at 30 mg/kg/day and more so by tacrolimus at 3 mg/kg/day. Immunophenotyping of lymphocyte sub-populations in spleen and lymph node indicated a decrease in T lymphocytes with pimecrolimus at 30 mg/kg/day, tacrolimus and CsA, whereas these changes were marginal for pimecrolimus at 10 mg/kg/day. Immunophenotyping of peripheral white blood cells (WBC) revealed a decrease in the absolute number of T lymphocytes with all three test items. In comparison with non-immunised animals, a slight increase in absolute numbers of T lymphocytes was observed in KLH-immunised animals treated with pimecrolimus at 10 or 30 mg/kg/day. In conclusion, the ability of the immune system to respond to KLH was not affected by pimecrolimus at 10 mg/kg/day whereas a decrease in immune function was noted in the other groups as follows: pimecrolimus (30 mg/kg/day) < tacrolimus (3 mg/kg/day) < CsA (20 mg/kg/day).
钙调神经磷酸酶抑制剂环孢素A（CsA）、他克莫司（FK506）和吡美莫司（ASM981）已分别上市用于口服治疗银屑病和特应性皮炎以及外用治疗特应性皮炎。本研究在大鼠用钥孔戚血蓝蛋白（KLH）免疫后，研究了这些治疗对免疫反应的影响。雄性大鼠（每组10只）分别以10或30mg/kg/天的剂量口服吡美莫司、3mg/kg/天的剂量口服他克莫司或20mg/kg/天的剂量口服CsA，持续4周。对照动物同样仅接受赋形剂。每组的最后5只动物分别在第16天和第24天用KLH进行免疫和激发。最后一次注射8天后，通过检测血清中KLH特异性抗体以及检查KLH激发部位的细胞浸润来研究免疫功能。此外，通过对血液中或驻留在淋巴组织中的淋巴细胞亚群进行定量，建立了功能和结构变化之间的相关性。在用KLH免疫的大鼠中，CsA导致KLH特异性IgM和IgG产生完全受到抑制，而只有IgG产生受到30mg/kg/天的吡美莫司的影响，3mg/kg/天的他克莫司对其影响更大。脾脏和淋巴结中淋巴细胞亚群的免疫表型分析表明，30mg/kg/天的吡美莫司、他克莫司和CsA会使T淋巴细胞减少，而10mg/kg/天的吡美莫司引起的这些变化较小。外周白细胞（WBC）的免疫表型分析显示，所有三个受试物都会使T淋巴细胞的绝对数量减少。与未免疫的动物相比，在以10或30mg/kg/天的剂量接受吡美莫司治疗的用KLH免疫的动物中，观察到T淋巴细胞的绝对数量略有增加。总之，10mg/kg/天的吡美莫司不影响免疫系统对KLH的反应能力，而其他组的免疫功能下降情况如下：吡美莫司（30mg/kg/天）<他克莫司（3mg/kg/天）<环孢素A（20mg/kg/天）。
