Sensitivity of baboon lymphocytes to cyclosporin A and FK 506: relative resistance of alloactivated cells to CyA

The interspecies differences in CyA pharmacokinetics necessitate the establishment of optimal immunosuppressive doses in the baboon, especially as its use as host for preclinical xenografts is anticipated. We assessed the immunosuppressive effects of CyA and FK 506 on lymphocytes from charma baboons, using human cells for comparison. At concentrations up to 100 mol/l, neither drug was toxic to lymphocytes. FK 506 inhibited baboon and human lymphocyte proliferation and IL-2 synthesis equally. In contrast, approximately four times higher doses of CyA were needed to inhibit baboon lymphocytes responding to alloantigens. This may explain the inadequate immunosuppression of baboon graft recipients treated with clinically acceptable doses of CyA. We propose that CyA whole blood target levels of ±1500 ng/ml should be used in this species and we provide evidence that chacma baboons are able to tolerate such doses without nephroxicity.     

The distinct effects of FK506 on the activation, proliferation, and differentiation of human B lymphocytes.

We examined the effect of FK506 on the activation, proliferation and differentiation of human B lymphocytes in vitro. FK506 inhibited the proliferative response of resting B cells induced by Staphylococcus aureus Cowan strain I (SAC) and phorbol myristate acetate (PMA) in a dose-dependent manner. Inhibition of cell proliferation by FK506 was caused by a selective block of G0 to G1 phase transition leading to cell arrest. In addition, the proliferative response of in vivo-activated B cells and lymphokine-driven B cell proliferation were also found to be sensitive to FK506. Interestingly, FK506 did not affect the expression of activation antigens such as CD23, IL-2 receptor (CD25), and transferrin receptor (CD71). Finally, FK506 had little effect on B cell antibody generation in a T cell-independent system. Conversely, FK506 suppressed neither proliferation nor immunoglobulin secretion in a human B lymphoblastoid cell line. These results indicate that FK506 has discrete effects on the different stages of the B cell maturation.     

他克莫司对肝移植受者外周血T淋巴细胞亚群及共刺激分子表达的影响

目的 探讨他克莫司（FK506）对肝移植受者外周血T淋巴细胞亚群及其表面共刺激分子表达的影响。方法 采用荧光标记单克隆抗体和流式细胞技术，测定术后采用FK506治疗的肝移植受者（FK506治疗组）在用FK506后1、2、3、4周时的外周血T淋巴细胞亚群及其表面共刺激分子CD28、CD152和ICOS分子的表达情况，以健康志愿者（健康对照组）和患终末期肝脏疾病拟行肝移植者（肝病对照组）为对照。结果 CD3^＋T淋巴细胞在各组间的差异均无统计学意义（P〉0．05）。经FK506治疗后，肝移植患者的CD4^＋T淋巴细胞逐渐减少，CD8^＋T淋巴细胞逐渐增加，并恢复至健康对照组水平（P〉0．05）。FK506治疗组T淋巴细胞亚群表面CD28分子和ICOS分子表达逐渐下降，并明显低于健康对照组（P〈0．05），而CD152分子表达增加，且明显高于健康对照组（P〈0．05）；其ICOS分子表达水平的下降晚于CD28分子，CD4^＋CD28^＋T淋巴细胞、CD8^＋CD28^＋T淋巴细胞和CD4^＋ICOS^＋T淋巴细胞均呈现相近的变化规律。结论 FK506能迅速纠正移植受者T淋巴细胞亚群紊乱，并抑制正性共刺激分子CD28和ICOS的表达，促进负性共刺激分子CD152的表达。