Université François Rabelais, Tours, France; CHRU Tours, Département de Néphrologie et Immunologie Clinique, Tours, France.
Transpl Immunol. 2013 Mar;28(2-3):120-6. doi: 10.1016/j.trim.2013.03.001. Epub 2013 Mar 16.
Rabbit antithymocyte globulin (rATG; Thymoglobulin(®)) is currently used to prevent acute rejection in kidney transplantation. The dose and regimen of rATG have not been optimized. Moreover, the impact of different treatment regimens on T-cell phenotype reconstitution remains unknown. We conducted a prospective randomized study of 17 renal transplant patients to determine the pharmacokinetics of total and active (bound to human cells) rATG and T-cell phenotype reconstitution after rATG administration. Patients received rATG at a total dose of 6mg/kg, administered either as 1.5mg/kg/day on days 0-3 (Group 1, n=8) or 3mg/kg on days 0 and 3 (Group 2, n=9). All patients received tacrolimus, mycophenolate mofetil and steroids. Blood samples were assayed for total rATG by enzyme linked immunosorbent assay and active rATG by flow cytometry. Maximum concentrations and terminal half-lives were similar between the two groups but at month 3 Group 1 had significantly lower values for total rATG (concentration was 6.2±1.1μg/mL versus 10.2±2.9μg/mL in Group 2, p=0.027) and total rATG dose-normalized AUC (374±83dayg/mL versus 508±149dayg/mL in Group 2, p=0.046). Time to sub-therapeutic levels (<1μg/mL) of active rATG was significantly shorter in Group 1 (18.75±6.9days versus 20±7.5days in Group 2, p<0.001). rATG induced significant depletion followed by slow reconstitution of CD3(+), CD4(+) and CD8(+) cells, with no marked differences between groups. B-cell count was unaffected, whereas CD3(-)CD56(+) NK-cell depletion was observed in both groups. rATG induced a significant decrease in the proportion of naïve CD4(+) T-cells, which plateaued after month 1 in Group 1 and after month 6 in Group 2. The proportion of central memory CD4(+) T-cells increased to a similar extent in both groups (Group 1: 38±18% at baseline, 74±23% at one year, p=0.009; Group 2: 32±14% at baseline, 65±14% at one year, p=0.001). In conclusion, our results suggest that the dosing regimen for rATG induction influences pharmacokinetic parameters without affecting the quality of immune reconstitution.
兔抗胸腺细胞球蛋白（rATG；Thymoglobulin(®)）目前用于预防肾移植中的急性排斥反应。rATG 的剂量和方案尚未得到优化。此外，不同治疗方案对 T 细胞表型重建的影响尚不清楚。我们进行了一项前瞻性随机研究，纳入 17 例肾移植患者，以确定 rATG 给药后总 rATG 和活性（与人细胞结合）rATG 的药代动力学和 T 细胞表型重建。患者接受 rATG 总量 6mg/kg，分为两组：第 0-3 天每天 1.5mg/kg（第 1 组，n=8）或第 0 和 3 天各 3mg/kg（第 2 组，n=9）。所有患者均接受他克莫司、霉酚酸酯和皮质类固醇治疗。通过酶联免疫吸附试验检测总 rATG，通过流式细胞术检测活性 rATG。两组间最大浓度和终末半衰期相似，但第 3 个月时第 1 组总 rATG （浓度分别为 6.2±1.1μg/mL 和 10.2±2.9μg/mL，p=0.027）和总 rATG 剂量标准化 AUC（分别为 374±83dayg/mL 和 508±149dayg/mL，p=0.046）明显较低。第 1 组达到亚治疗水平（<1μg/mL）的活性 rATG 的时间明显短于第 2 组（18.75±6.9 天和 20±7.5 天，p<0.001）。rATG 诱导 CD3(+), CD4(+) 和 CD8(+)细胞明显耗竭，随后缓慢重建，两组间无明显差异。B 细胞计数不受影响，但两组均观察到 CD3(-)CD56(+)NK 细胞耗竭。rATG 诱导初始 CD4(+)T 细胞比例显著下降，第 1 组在 1 个月后和第 2 组在 6 个月后达到平台期。两组中央记忆 CD4(+)T 细胞比例均增加至相似水平（第 1 组：基线时 38±18%，1 年时 74±23%，p=0.009；第 2 组：基线时 32±14%，1 年时 65±14%，p=0.001）。总之，我们的结果表明，rATG 诱导的剂量方案影响药代动力学参数，而不影响免疫重建的质量。
