环孢素A、C、D及其代谢产物M1、M17和M21免疫抑制特性的体外和体内比较研究

In vitro and in vivo comparative studies on immunosuppressive properties of cyclosporines A, C, D and metabolites M1, M17 and M21.

作者信息

Sadeg N, Pham-Huy C, Rucay P, Righenzi S, Halle-Pannenko O, Claude J R, Bismuth H, Duc H T

机构信息

Laboratoire de Toxicologie, Faculté de Pharmacie, Paris, France.

出版信息

Immunopharmacol Immunotoxicol. 1993 Mar-Jun;15(2-3):163-77. doi: 10.3109/08923979309025992.

DOI:10.3109/08923979309025992

PMID:8349948

Abstract

Cyclosporine A (CsA) and its major metabolites: M1, M17 and M21 and two analogues: cyclosporines C (CsC) and D (CsD), were studied for their capacity to interfere with different in vitro activation pathways. Their inhibition potentials against the reaction of Graft-versus-Host (GvH) were also studied. The results showed: CsA, CsC and metabolite M17 were the most active compounds upon the inhibition of lymphocyte proliferation induced by different mitogens (ConA, PHA, PWM) and also on the proliferation of mixed lymphocyte cultures (MLC). The same results were observed concerning the direct activation by protein kinase C using a combined action of phorbol ester + calcium ionophore. In vivo using local GvH reaction, CsA and CsC proved more active than M17 in the two different combinations: H-2d --> (H-2b x H-2d)F1 and H-2k --> (H-2b x H-2k)F1 CsD and two metabolites M1 and M21 showed no or weak immunosuppressive effects. Overall, the immunosuppressive potency of six compounds could be schematized as: CsA > or = CsC > M17 > M1 > or = CsD > M21.

摘要

研究了环孢素A（CsA）及其主要代谢产物：M1、M17和M21，以及两种类似物：环孢素C（CsC）和环孢素D（CsD）干扰不同体外激活途径的能力。还研究了它们对移植物抗宿主反应（GvH）的抑制潜力。结果表明：CsA、CsC和代谢产物M17是抑制由不同有丝分裂原（刀豆蛋白A、植物血凝素、美洲商陆丝裂原）诱导的淋巴细胞增殖以及混合淋巴细胞培养（MLC）增殖的最具活性的化合物。关于使用佛波酯+钙离子载体的联合作用通过蛋白激酶C进行的直接激活，也观察到了相同的结果。在体内使用局部GvH反应，在两种不同组合中，CsA和CsC比M17更具活性：H-2d→（H-2b×H-2d）F1和H-2k→（H-2b×H-2k）F1。CsD以及两种代谢产物M1和M21显示无免疫抑制作用或免疫抑制作用较弱。总体而言，六种化合物的免疫抑制效力可概括为：CsA≥CsC＞M17＞M1≥CsD＞M21。