Bavandi A, Fahrngruber H, Aschauer H, Hartmann B, Meingassner J G, Kalthoff F S
Novartis Institutes for BioMedical Research, Brunnerstrasse 59, A 1235 Vienna, Austria.
J Dermatol Sci. 2006 Aug;43(2):117-26. doi: 10.1016/j.jdermsci.2006.04.001. Epub 2006 Jun 27.
As reported previously, oral administration of the calcineurin inhibitors (CNI) pimecrolimus and tacrolimus resulted in equipotent inhibition of the elicitation phase of contact hypersensitivity (CHS) in mice. The sensitization phase was inhibited by tacrolimus but was unaffected by pimecrolimus, even at higher doses.
The kinetics of lymph node hyperplasia and up-regulation of T and B cell activation antigens were analyzed to obtain a better understanding of the divergent CNI profile in CHS.
Lymph node (LN) cells of CNI-untreated and treated mice were examined with flow cytometry at various time points after sensitization with oxazolone. LN hyperplasia and drug levels were also determined.
Sensitization induced a higher portion of LN cells expressing the activation antigens CD25, CD69 and CD134 and an increase in activated B cells (B220(+)/CD40(+)) compared to naïve mice. Up-regulation of these markers was completely or profoundly blocked with tacrolimus, whereas pimecrolimus at the three-fold higher dose caused significantly less inhibition. Tacrolimus also completely blocked the sensitization-associated increase of CD11c(+) antigen presenting cells (APC) in LN, whereas pimecrolimus showed significantly less inhibition. In contrast to tacrolimus, LN weight and cellularity were not affected by pimecrolimus at any time point after sensitization. Concentration of tacrolimus in blood and in the draining LN substantially exceeded that of pimecrolimus by factors 6.7-14 and 5.6-5.8, respectively, at the same dose levels.
In contrast to tacrolimus, systemic treatment of mice with pimecrolimus only weakly interferes with lymphocyte activation and does not affect hyperplasia of the draining lymph nodes during sensitization.
如先前报道，口服钙调神经磷酸酶抑制剂（CNI）吡美莫司和他克莫司对小鼠接触性超敏反应（CHS）激发阶段的抑制作用相当。他克莫司可抑制致敏阶段，而吡美莫司即使在高剂量时对此阶段也无影响。
分析淋巴结增生动力学以及T和B细胞活化抗原的上调情况，以更好地理解CHS中不同CNI的作用特点。
在用恶唑酮致敏后的不同时间点，通过流式细胞术检测未用CNI处理及用CNI处理的小鼠的淋巴结（LN）细胞。同时测定淋巴结增生情况和药物水平。
与未致敏小鼠相比，致敏诱导表达活化抗原CD25、CD69和CD134的LN细胞比例更高，且活化B细胞（B220(+)/CD40(+)）增加。他克莫司可完全或显著阻断这些标志物的上调，而吡美莫司剂量高出三倍时，抑制作用明显较弱。他克莫司还可完全阻断致敏相关的LN中CD11c(+)抗原呈递细胞（APC）的增加，而吡美莫司的抑制作用明显较弱。与他克莫司不同，致敏后任何时间点吡美莫司均不影响LN重量和细胞数量。在相同剂量水平下，血液和引流LN中他克莫司的浓度分别比吡美莫司高6.7 - 14倍和5.6 - 5.8倍。
与他克莫司不同，吡美莫司全身治疗小鼠时仅微弱干扰淋巴细胞活化，且不影响致敏期间引流淋巴结的增生。
