Nashan B, Schwinzer R, Schlitt H J, Wonigeit K, Pichlmayr R
Klinik für Abdominal- und Transplantationschirurgie, Medizinische Hochschule Hannover, Germany.
Transpl Immunol. 1995 Sep;3(3):203-11. doi: 10.1016/0966-3274(95)80026-3.
The immunological effects of therapeutic monoclonal antibodies (mAbs) depend upon their interaction with the target structure as well as the isotype of the mAb which is responsible for the binding to Fc receptors of accessory cells. The aim of the presented analysis was the evaluation of the in vivo immunosuppressive effect of BT 563, a mAb directed to the alpha-chain of the interleukin-2 receptor (IL-2R). Thirty-eight patients following liver transplantation were treated prophylactically for 12 days with 10 mg/day BT 563 (clinical phase II and III study). As baseline immunosuppression cyclosporin (CyA) and low dose steroids were administered. BT 563 levels, lymphocyte subpopulations, levels of soluble CD25 and Fc receptor polymorphism were evaluated and compared to the clinical outcome. Preoperatively in all patients a small subset of CD45R0+ cells expressed CD25 with detectable density. These cells were coated by BT 563. There was no evidence for depletion of IL-2R+ cells or modulation of the IL-2R. During therapy stable levels of the soluble IL-2R were measured in patient sera. Throughout the therapy high levels of unbound BT 563 were found in sera, suggesting that IL-2R newly expressed on cells activated by the allograft could also be inhibited by BT 563. No acute rejections were observed in these patients and no side effects of BT 563 were noted. There were only minor bacterial infections, while mycotic or viral infections did not appear. Administration of BT 563 together with CyA and low dose steroids to liver allografted patients represents a safe and effective protocol. Its action is likely to be mediated by turning off the pathway of signal transduction of the IL-2R in T-cells by the antibody while IL-2 gene transcription is simultaneously modified by CyA and steroids. The addition of all three immunosuppressive mechanisms is suggested to lead to a state of anergy during mAb application that is reversible at the end of antibody therapy but does not lead to rebound rejections. Analysis of the phenotype of CD25+ cells showed that they preferentially belonged to the CD45R0+ cell type. Thus we assume that BT 563 specifically turns off preactivated cells enabling rather selective and effective immunoprophylaxis in liver allografted patients.
治疗性单克隆抗体（mAb）的免疫效应取决于其与靶结构的相互作用以及负责与辅助细胞的Fc受体结合的mAb同种型。本分析的目的是评估BT 563的体内免疫抑制作用，BT 563是一种针对白细胞介素-2受体（IL-2R）α链的单克隆抗体。38例肝移植患者接受了为期12天的预防性治疗，每天使用10 mg BT 563（临床II期和III期研究）。作为基线免疫抑制，给予环孢素（CyA）和低剂量类固醇。评估了BT 563水平、淋巴细胞亚群、可溶性CD25水平和Fc受体多态性，并与临床结果进行了比较。术前，所有患者中一小部分CD45R0+细胞表达可检测密度的CD25。这些细胞被BT 563包被。没有证据表明IL-2R+细胞耗竭或IL-2R受到调节。治疗期间，在患者血清中检测到可溶性IL-2R的稳定水平。在整个治疗过程中，血清中发现高水平的未结合BT 563，这表明同种异体移植物激活的细胞上新表达的IL-2R也可能被BT 563抑制。这些患者未观察到急性排斥反应，也未发现BT 563的副作用。仅出现轻微的细菌感染，而霉菌或病毒感染未出现。将BT 563与CyA和低剂量类固醇联合应用于肝移植患者是一种安全有效的方案。其作用可能是通过抗体关闭T细胞中IL-2R的信号转导途径，同时CyA和类固醇对IL-2基因转录进行修饰来介导的。建议这三种免疫抑制机制共同作用，在应用单克隆抗体期间导致无反应状态，在抗体治疗结束时这种状态是可逆的，但不会导致反弹性排斥反应。对CD25+细胞表型的分析表明，它们优先属于CD45R0+细胞类型。因此，我们假设BT 563特异性地关闭预激活细胞，从而在肝移植患者中实现相当选择性和有效的免疫预防。
