Flechner S M, Goldfarb D A, Fairchild R, Modlin C S, Fisher R, Mastroianni B, Boparai N, O'Malley K J, Cook D J, Novick A C
Department of Urology, Cleveland Clinic Foundation, Ohio 44195, USA.
Transplantation. 2000 Jun 15;69(11):2374-81. doi: 10.1097/00007890-200006150-00027.
We attempted to minimize the undesired side effects and maximize the benefit of OKT3 induction therapy in renal transplantation.
One hundred and one recipients of kidney-only transplants were randomized to three groups. Each received low-dose 2.5-mg OKT3 induction for 7-14 days, but different premedication on days 0, 1, and 2. Group I was given 250 mg i.v. methylprednisolone at 1 and 6 hr, and group II received another 500 mg at 1 hr before initial OKT3. Group III received Atgam 15 mg/kg on day 0 and began OKT3 on day 1. A CD3+ T-cell cut-off of 50/mm3 was used to guide therapy. Maintenance therapy included cyclosporine and steroids for each patient. However, groups I and II were also given mycophenolate mofetil, and group III received azathioprine as a third agent. All rejections were biopsy confirmed and Banff scored.
No differences in demographic or transplant characteristics were noted between groups I, II, and III, and mean follow-up was 25.7 (1-38) months. There was no significant difference in actuarial patient (90%, 91%, 94%) or graft survival (83%, 88%, 84%) at 3 years between the respective groups. Mean creatinine values and infectious complications were similar for each group. No patient experienced acute rejection during induction, and eight patients required dose escalation to sustain suppression of CD3 counts. The incidence of acute rejection at 6 and 12 months was significantly (P=0.004) greater in group III (38.2, 44.1%) than in either group I (15.1, 18.1%) or group II (14.7, 17.6%); relative risk 1.988 (95% CI 1.012-3.906). Formation of anti-OKT3 antibody was significantly (P=0.006) greater in group III (26.5%) than in group I (6%) or group II (2.9%). Group I recipients enjoyed significantly (P=0.001) fewer (2.17) OKT3 side effects on days 0, 1, and 2 than group II (3.03) or group III (2.49), and contained the largest number (61%) of recipients who experienced no side effects. Group I also exhibited the most suppressed profile of OKT3-induced release of tumor necrosis factor-alpha (P=0.006), interferon-gamma (P=NS), and interleukin-6 (P=0.01) on days 0 and 1.
Low-dose 2.5-mg OKT3 with pretreatment of split-dose steroids on days 0, 1, and 2 provides the most effective method for OKT3 induction, which minimizes side effects for most patients. Subsequent maintenance therapy with cyclosporine, mycophenolate mofetil, and steroids provides effective rejection prophylaxis without increased complications for up to 3 years. Predepletion of T cells before exposure to OKT3 does not prevent cytokine release.
我们试图将肾移植中OKT3诱导治疗的不良副作用降至最低，并使获益最大化。
101例单纯肾移植受者被随机分为三组。每组均接受2.5毫克低剂量OKT3诱导治疗7 - 14天，但在第0、1和2天的预处理不同。第一组在第1小时和第6小时静脉注射250毫克甲泼尼龙，第二组在首次使用OKT3前1小时额外接受500毫克。第三组在第0天接受15毫克/千克的抗胸腺细胞球蛋白，并在第1天开始使用OKT3。以CD3 + T细胞计数低于50/mm³作为指导治疗的标准。每位患者的维持治疗包括环孢素和类固醇。然而，第一组和第二组还给予霉酚酸酯，第三组接受硫唑嘌呤作为第三种药物。所有排斥反应均经活检证实并进行班夫评分。
第一、二、三组在人口统计学或移植特征方面无差异，平均随访时间为25.7（1 - 38）个月。三组在3年时的实际患者生存率（90%、91%、94%）或移植物生存率（83%、88%、84%）无显著差异。每组的平均肌酐值和感染并发症相似。诱导期无患者发生急性排斥反应，8例患者需要增加剂量以维持对CD3计数的抑制。第三组在6个月和12个月时的急性排斥反应发生率（38.2%，44.1%）显著高于第一组（15.1%，18.1%）或第二组（14.7%，17.6%）（P = 0.004）；相对风险为1.988（95%置信区间1.012 - 3.906）。第三组（26.5%）抗OKT3抗体的形成显著高于第一组（6%）或第二组（2.9%）（P = 0.006）。在第0、1和2天，第一组受者的OKT3副作用（2.17）显著少于第二组（3.03）或第三组（2.49）（P = 0.001），且无副作用的受者数量最多（61%）。在第0天和第1天，第一组OKT3诱导的肿瘤坏死因子-α（P = 0.006）、干扰素-γ（P = 无显著性差异）和白细胞介素-6（P = 0.01）释放的抑制程度也最高。
在第0、1和2天使用低剂量2.5毫克OKT3并联合分次剂量类固醇进行预处理，为OKT3诱导提供了最有效的方法，可使大多数患者的副作用降至最低。随后使用环孢素、霉酚酸酯和类固醇进行维持治疗，可有效预防排斥反应，且在长达3年的时间内不会增加并发症。在接触OKT3之前对T细胞进行预清除并不能防止细胞因子的释放。
