Cantarovich D, Le Mauff B, Hourmant M, Giral M, Denis M, Hirn M, Jacques Y, Soulillou J P
Service de Néphrologie-Immunologie Clinique, C.H.R., Nantes, France.
Transplantation. 1989 Mar;47(3):454-7. doi: 10.1097/00007890-198903000-00011.
Monoclonal antibodies (MoAbs) against human interleukin 2 receptor (IL-2-R) have been shown to prevent early kidney rejection in animals and humans. We report here the effect of an anti-IL-2-R MoAb (33B3.1) inhibiting IL-2 binding high-affinity sites on activated lymphocytes in 10 declared acute rejection episodes of first cadaveric kidney grafts. Six patients were under cyclosporine treatment only at the time of diagnosis of the rejection. All rejection episodes but one were biopsy-proved cellular rejections. Treatment consisted of intravenous infusions of 33B3.1 at 20 mg/day x 2 days, followed by 10 mg/day for 8 additional days. In case of MoAb ineffectiveness at day 5, anti-IL-2-R MoAb was discontinued and a rescue treatment of corticosteroid boluses (CSb) was given. If not, in all cases corticosteroids (CS) were given (1 mg/kg) at the end of MoAb treatment (day 10) and tapered off thereafter. Two rejection episodes immediately responded to 33B3.1 treatment. During 33B3.1 treatment four other patients had only a stabilization of their blood creatinine concentration, which nevertheless returned to prerejection levels after day 10 when anti-IL-2-R was discontinued and CS administered at 1 mg/kg (no rescue treatment). The four remaining patients had an increase of their blood creatinin levels at day 5 despite 33B3.1 treatment, and their renal function only improved with CSb rescue treatment. One of these patients lost the graft despite rescue treatment, as well as a 9-day course of antithymocyte globulin. Trough levels of MoAb reached a plateau as early as day 2 (approximately 6 micrograms/ml). All patients developed antibodies (IgM and IgG) after day 14. In no instance could unresponsiveness be related to low circulating 33B3.1 trough levels or to early host anti-MoAb immune response (IgM or IgG). We conclude that 33B3.1, known to be effective in preventing early rejection, has only inconsistent and/or incomplete effects on the ongoing rejection process. Our data suggest that once IL-2-dependent clones are expanded in the rejected graft, interference with IL-2/IL-2-R signals does not block the effector mechanisms sustaining acute rejection.
抗人白细胞介素2受体（IL-2-R）的单克隆抗体（MoAbs）已被证明可预防动物和人类的早期肾移植排斥反应。我们在此报告一种抗IL-2-R单克隆抗体（33B3.1）在10例首次尸体肾移植的明确急性排斥反应中，对抑制活化淋巴细胞上IL-2高亲和力结合位点的作用。6例患者在诊断排斥反应时仅接受环孢素治疗。除1例排斥反应外，所有排斥反应均经活检证实为细胞性排斥反应。治疗方法为静脉输注33B3.1，剂量为20mg/天，共2天，随后10mg/天，持续8天。若在第5天单克隆抗体无效，则停用抗IL-2-R单克隆抗体，并给予大剂量皮质类固醇（CSb）抢救治疗。若有效，则在单克隆抗体治疗结束时（第10天）给予所有患者皮质类固醇（CS）（1mg/kg），此后逐渐减量。2例排斥反应立即对33B3.1治疗有反应。在33B3.1治疗期间，另外4例患者的血肌酐浓度仅保持稳定，但在第10天停用抗IL-2-R并给予1mg/kg的CS后（未进行抢救治疗），血肌酐浓度恢复到排斥反应前水平。其余4例患者尽管接受了33B3.1治疗，但在第5天血肌酐水平仍升高，其肾功能仅在CSb抢救治疗后有所改善。其中1例患者尽管接受了抢救治疗以及9天疗程的抗胸腺细胞球蛋白治疗，仍失去了移植肾。单克隆抗体的谷浓度早在第2天就达到平台期（约6μg/ml）。所有患者在第14天后均产生了抗体（IgM和IgG）。在任何情况下，无反应性均与循环中33B3.1谷浓度低或早期宿主抗单克隆抗体免疫反应（IgM或IgG）无关。我们得出结论，已知能有效预防早期排斥反应的33B3.1，对正在进行的排斥反应过程仅有不一致和/或不完全的作用。我们的数据表明，一旦IL-2依赖克隆在被排斥的移植物中扩增，干扰IL-2/IL-2-R信号并不能阻断维持急性排斥反应的效应机制。
