Eason J D, Pascual M, Wee S, Farrell M, Phelan J, Boskovic S, Blosch C, Mohler K M, Cosimi A B
Transplantation Unit, Massachusetts General Hospital, Boston, USA.
Transplantation. 1996 Jan 27;61(2):224-8. doi: 10.1097/00007890-199601270-00011.
Tumor necrosis factor alpha (TNFa) has been shown to be the primary cytokine responsible for the OKT3-induced acute clinical syndrome (OKT3-ACS). Recombinant human soluble tumor necrosis factor receptor (TNFR:Fc) is a dimer of the p80 TNF receptor, which binds both TNFa and lymphotoxin (LT). Renal allograft recipients undergoing OKT3 therapy for steroid-resistant rejection were randomized to receive OKT3 alone or in combination with TNFR:Fc to determine its safety and efficacy in decreasing the severity of OKT3-ACS and in restoring renal function. Six of 12 patients were given TNFR:Fc prior to each of the first two injections of OKT3. All patients were monitored for manifestations of OKT3-ACS and changes in renal function. In addition, serial serum samples were assayed for TNFa and TNFR:Fc levels (ELISA) and TNFa bioactivity (L929). No adverse side effects were identified in patients receiving TNFR:Fc. Patients treated with TNFR:Fc had significantly fewer symptoms by day 2 of OKT3, and had a lower overall incidence of chills and arthralgias. Renal dysfunction reversed within 24 hr in the TNFR:Fc-treated group in contrast to the 48-72-hr delay in the control group. Antigenic TNFa levels increased in the control group from < 10 pg/ml pre OKT3 to a mean peak level of 30 +/- 13 pg/ml on day 1 and decreased to pretreatment levels by day 2. TNFR:Fc-treated patients had a mean peak TNFa level of 235 +/- 135 pg/ml, suggesting a carrier effect of TNFR:Fc. In contrast, bioactivity was barely detectable (mean 20 +/- 14 pg/ml) in the day 1 samples from TNFR:Fc-treated patients, whereas significant bioactivity (peak mean 60 +/- 35 pg/ml) was detected in sera from control patients. TNF receptor levels reached 600 ng/ml in treated patients and remained elevated for up to 18 days confirming the long half-life of TNFR:Fc. This phase 1 trial demonstrates that TNFR:Fc is well tolerated and may limit the severity of OKT3-ACS. The most significant observation was a more rapid improvement in renal function in the TNFR:Fc-treated patients. The absence of TNFa bioactivity indicates that TNFR:Fc functions as a TNF antagonist. Further evaluation of higher doses of TNFR:Fc in OKT3-treated patients is currently in progress.
肿瘤坏死因子α（TNFα）已被证明是导致OKT3诱导的急性临床综合征（OKT3-ACS）的主要细胞因子。重组人可溶性肿瘤坏死因子受体（TNFR:Fc）是p80 TNF受体的二聚体，可结合TNFα和淋巴毒素（LT）。因激素抵抗性排斥反应而接受OKT3治疗的肾移植受者被随机分为单独接受OKT3或联合TNFR:Fc治疗，以确定其在降低OKT3-ACS严重程度和恢复肾功能方面的安全性和有效性。12例患者中有6例在最初两次注射OKT3之前接受了TNFR:Fc治疗。所有患者均监测OKT3-ACS的表现和肾功能变化。此外，还对系列血清样本进行了TNFα和TNFR:Fc水平（酶联免疫吸附测定法）以及TNFα生物活性（L929细胞）检测。接受TNFR:Fc治疗的患者未发现不良副作用。接受TNFR:Fc治疗的患者在OKT3治疗第2天时症状明显较少，寒战和关节痛的总体发生率较低。与对照组48 - 72小时的延迟相比，TNFR:Fc治疗组的肾功能障碍在24小时内得到逆转。对照组中抗原性TNFα水平从OKT3治疗前的<10 pg/ml在第1天升至平均峰值水平30±13 pg/ml，并在第2天降至治疗前水平。接受TNFR:Fc治疗的患者TNFα平均峰值水平为235±135 pg/ml，提示TNFR:Fc具有载体效应。相比之下，接受TNFR:Fc治疗患者第1天样本中的生物活性几乎检测不到（平均20±14 pg/ml），而对照组患者血清中检测到显著的生物活性（峰值平均60±35 pg/ml）。接受治疗患者的TNF受体水平达到600 ng/ml，并在长达18天内保持升高，证实了TNFR:Fc的长半衰期。这项1期试验表明TNFR:Fc耐受性良好，可能会减轻OKT3-ACS的严重程度。最显著的观察结果是TNFR:Fc治疗的患者肾功能改善更快。TNFα生物活性的缺乏表明TNFR:Fc起到TNF拮抗剂的作用。目前正在对接受OKT3治疗的患者中更高剂量的TNFR:Fc进行进一步评估。
