Norin A J, Kamholz S L, Pinsker K L, Emeson E E, Veith F J
Transplantation. 1986 Nov;42(5):466-72.
Although cyclosporine (CsA) is widely used as the primary agent for inhibiting the rejection of organ allografts in man, the ideal immunosuppressive regimen for utilizing this drug is still uncertain. To investigate this question, a concanavalin A (con A)-dependent cell-mediated cytotoxicity (CDCMC) assay was used to examine the development of intragraft and peripheral blood cytolytic T lymphocyte activity during CsA dose tapering. These studies were conducted in a canine single-lung transplantation model that facilitates serial examination of intragraft effector cells by bronchoalveolar lavage (BAL). A remarkable correlation of increased intragraft CDCMC and clinical evidence of lung allograft rejection was observed during CsA dose tapering in some recipients. In other recipients CDCMC remained low and evidence of rejection was not observed during drug tapering. In contrast, peripheral blood CDCMC did not correlate well with evidence of rejection. Rejection phenomena observed after termination of CsA therapy were reversed by resumption of CsA treatment but were not reversed by administration of methylprednisolone. Furthermore, the increased level of CDCMC was diminished by reinstitution of CsA therapy at the initial dosage. Following termination of CsA therapy, a prolonged period of unresponsiveness was observed in nearly two-thirds of the recipients, and 60% of these latter dogs had unlimited survival of their lung allografts (median greater than 496 days). Intragraft CDCMC remained low during the periods of unresponsiveness and increased upon onset of rejection. We conclude that measurement of intragraft CDCMC is a useful in vitro method of monitoring lung allograft rejection, and therefore provides a technique for adjusting CsA dosage schedules to achieve maximally effective immunosuppression. The use of this assay for monitoring rejection of other organ grafts requires further investigation.
尽管环孢素（CsA）被广泛用作抑制人体器官移植排斥反应的主要药物，但使用该药物的理想免疫抑制方案仍不明确。为了研究这个问题，我们采用刀豆球蛋白A（Con A）依赖性细胞介导的细胞毒性（CDCMC）试验，来检测在CsA剂量逐渐减少期间移植组织内和外周血细胞溶解性T淋巴细胞活性的变化。这些研究是在犬单肺移植模型中进行的，该模型便于通过支气管肺泡灌洗（BAL）对移植组织内的效应细胞进行系列检查。在一些接受者中，观察到在CsA剂量逐渐减少期间，移植组织内CDCMC增加与肺移植排斥反应的临床证据之间存在显著相关性。在其他接受者中，CDCMC仍然很低，并且在药物减量期间未观察到排斥反应的证据。相比之下，外周血CDCMC与排斥反应的证据相关性不佳。CsA治疗终止后观察到的排斥现象，通过恢复CsA治疗得以逆转，但给予甲基强的松龙则不能逆转。此外，通过以初始剂量重新开始CsA治疗，CDCMC的升高水平降低。CsA治疗终止后，近三分之二的接受者出现了长时间的无反应期，其中60%的犬其肺移植存活时间无限制（中位数大于496天）。在无反应期，移植组织内CDCMC保持较低水平，而在排斥反应开始时升高。我们得出结论，测量移植组织内CDCMC是监测肺移植排斥反应的一种有用的体外方法，因此提供了一种调整CsA给药方案以实现最大有效免疫抑制的技术。将该试验用于监测其他器官移植的排斥反应需要进一步研究。
