Bouma G J, Hollander D A, van der Meer-Prins E M, van Bree S P, van Rood J J, van der Woude F J, Claas F H
Department of Immunohematology and Blood Bank, Leiden University Hospital, The Netherlands.
Transplantation. 1996 Nov 27;62(10):1422-9. doi: 10.1097/00007890-199611270-00008.
A maintenance immunosuppressive regimen of cyclosporine and steroids after renal transplantation has proven to be a successful policy to obtain long-term graft survival. However, serious side-effects are associated with this therapy; these include an increased risk for infections, cancer, and cardiovascular morbidity and mortality. Therefore, this pilot study was conducted to investigate the possibility of reducing the immunosuppressive load after transplantation. To this end, we tried to develop an in vitro assay to predict graft rejection after withdrawing steroids from the immunosuppressive therapy. Patients who had stable renal function at least one year after transplantation were randomly divided into a group that continued to receive standard immunosuppression of cyclosporine and steroids and a group to be withdrawn from steroid therapy, the latter group being the subject of the present study. Patients withdrawn from steroids were monitored closely and when a biopsy-proven rejection occurred, steroid treatment was reestablished. Blood was collected from patients preceding steroid withdrawal and at fixed time points thereafter. In case of suspected rejection, blood was also taken before biopsy, before steroid treatment was reestablished. In the in vitro limiting dilution analysis-assays cytotoxic T lymphocyte precursor frequencies directed against kidney donor HLA-antigens were determined, in the absence or presence of cyclosporine and several concentrations of prednisolone and the combination of these agents. Confirming earlier results, we found that the number of cyclosporine-resistant cytotoxic T lymphocytes increased prior to a rejection crisis, while they did not change or even decreased in patients who retained normal graft function after steroid withdrawal. More importantly, the results show that 10(-7) M prednisolone in vitro differentially affected donor-specific cytotoxic T lymphocyte precursor frequencies in patients who experienced a rejection crisis after steroid withdrawal, compared with those who remained to do well. This heterogeneity could be detected before the start of steroid withdrawal. Therefore, we conclude that the present data justify a prospective clinical trial to investigate the possible application of this in vitro assay to predict for which patients steroid withdrawal might be considered.
肾移植后采用环孢素和类固醇的维持性免疫抑制方案已被证明是实现长期移植物存活的成功策略。然而，这种治疗伴有严重的副作用；这些副作用包括感染、癌症以及心血管疾病发病率和死亡率增加的风险。因此，开展了这项试点研究以探讨降低移植后免疫抑制负荷的可能性。为此，我们试图开发一种体外检测方法，以预测免疫抑制治疗中停用类固醇后移植物的排斥反应。移植后至少一年肾功能稳定的患者被随机分为两组，一组继续接受环孢素和类固醇的标准免疫抑制治疗，另一组停用类固醇治疗，后一组为本研究的对象。停用类固醇的患者被密切监测，当经活检证实发生排斥反应时，重新开始类固醇治疗。在停用类固醇之前以及此后的固定时间点采集患者的血液。在疑似排斥反应的情况下，在活检前、重新开始类固醇治疗前也采集血液。在体外极限稀释分析检测中，测定在不存在或存在环孢素、几种浓度的泼尼松龙以及这些药物组合的情况下，针对肾脏供体 HLA 抗原的细胞毒性 T 淋巴细胞前体频率。与早期结果一致，我们发现，在排斥危机发生前，对环孢素耐药的细胞毒性 T 淋巴细胞数量增加，而在停用类固醇后移植肾功能正常的患者中，这些细胞数量没有变化甚至减少。更重要的是，结果表明，与那些情况良好的患者相比，体外浓度为 10(-7) M 的泼尼松龙对停用类固醇后发生排斥危机的患者的供体特异性细胞毒性 T 淋巴细胞前体频率有不同影响。这种异质性在停用类固醇开始前就能检测到。因此，我们得出结论，目前的数据证明有必要进行一项前瞻性临床试验，以研究这种体外检测方法在预测哪些患者可以考虑停用类固醇方面的可能应用。
