Cavazzana-Calvo M, André-Schmutz I, Hacein-Bey S, Schindler J, Vitetta H, Dupuis S, Quartier P, Chedeville G, Vilmer E, Casanova J L, Buffet R, Caillat-Zucman S, Radford I, Le Deist F, Fischer A
Laboratoire de Thérapie Cellulaire et Génique, Hôpital Necker Enfants Malades, 149, rue de Sèvres, 75015 Paris.
J Soc Biol. 2001;195(1):65-8.
The success of HSCT from HLA partially disparate donors depends on the development of new strategies able to efficiently prevent GVHD and to protect patients from infections and relapse. Using an immunotoxin (IT) directed against the alpha-chain (p55) of the human IL-2r (RFT5-SMPT-dgA), we have previously shown that it is possible to kill mature T cells activated towards a specific HLA complex by a one-way MLR. We designed a clinical trial assessing the effect of infusing increasing doses of T lymphocytes in the setting of children recipients of non HLA genetically identical HSCT. Thirteen patients have been enrolled from September 1998 to April 2000 and fourteen HSCT have been realized in 13 patients (pts). Donors were MUD in 3 cases and familial HLA partially disparate in the remaining cases. Allodepleted donor T cells were injected between day +14 and day +30 provided that ATG was undetectable in the serum and blood PMN counts was > 500/microliter. The mean age of these patients was 17 months (range 1 to 42). Diagnosis included immune deficient and malignant hemopathies. Three patients received 1 x 10(5) allodepleted T cell/kg, 7 patients received 4 x 10(5)/kg and 4 patients received 6 x 10(5)/kg allodepleted T cells. Full inhibition of MLR was achieved in 12 out of 14 cases. In two cases, a residual T cell reactivity to the recipient was observed (4 to 5%) and patients developed grade II aGVHD. aGVHD occurred in 4 out of 11 grafted patients (all grade II). No chronic GVHD has developed, so far. Three patients died from severe VOD or PHT at day +34, day 51 and day +166, while one infected patient by VZV, CMV and EBV before HSCT died 6 months after transplantation from meningoencephalitis and another patient died from relapse at day +291. The patient for which there was no engraftment died at day +48 from staphylococcus infection. Overall survival is 54%, with a median follow up of 8 months; the mean time to reach a blood lymphocyte count > 500 was 41 days, to reach a CD3 count > 300 microliters 63 days (20-111), CD4 > 200 microliters 97 days and positive mitogen-induced proliferation 90 days. In three patients, a tetanus-toxoid positive proliferation was detected before immunization. From this intermediate analysis, we conclude that 1) specific allodepletion is an effective approach to prevent aGVHD in a haploincompatible setting, 2) data on immunological reconstitution suggest that infused T cells do survive and expand. A higher number of patients must be enrolled to determine the optimal number of T cells to infuse.
来自HLA部分不匹配供者的造血干细胞移植（HSCT）的成功取决于能否开发出新的策略，以有效预防移植物抗宿主病（GVHD），并保护患者免受感染和复发。我们之前使用一种针对人白细胞介素-2受体α链（p55）的免疫毒素（IT）（RFT5-SMPT-dgA），证明通过单向混合淋巴细胞反应（MLR）能够杀死针对特定HLA复合体活化的成熟T细胞。我们设计了一项临床试验，评估在非HLA基因相同的HSCT儿童受者中输注递增剂量T淋巴细胞的效果。从1998年9月至2000年4月共入组13例患者，13例患者（pts）共进行了14次HSCT。3例供者为无关供者（MUD），其余为家族性HLA部分不匹配。在血清中检测不到抗胸腺细胞球蛋白（ATG）且血液中性粒细胞计数>500/微升的情况下，在+14天至+30天之间注射去除同种异体反应性的供者T细胞。这些患者的平均年龄为17个月（范围1至42个月）。诊断包括免疫缺陷和恶性血液病。3例患者接受1×10⁵去除同种异体反应性的T细胞/kg，7例患者接受4×10⁵/kg，4例患者接受6×10⁵/kg去除同种异体反应性的T细胞。14例中有12例实现了对MLR的完全抑制。2例中观察到对受者有残余T细胞反应性（4%至5%），患者发生了II级急性移植物抗宿主病（aGVHD）。11例移植患者中有4例发生了aGVHD（均为II级）。迄今为止，尚未发生慢性GVHD。3例患者分别在+34天、51天和+166天死于严重的肝静脉闭塞病（VOD）或门静脉高压（PHT），1例在HSCT前感染水痘带状疱疹病毒（VZV）、巨细胞病毒（CMV）和EB病毒的患者在移植后6个月死于脑膜脑炎，另1例患者在+291天死于复发。未植入的患者在+48天死于葡萄球菌感染。总体生存率为54%，中位随访时间为8个月；达到血液淋巴细胞计数>500的平均时间为41天，达到CD3计数>300/微升的时间为63天（20 - 111天），CD4>200/微升的时间为97天，有丝分裂原诱导的增殖阳性的时间为90天。3例患者在免疫前检测到破伤风类毒素阳性增殖。从这项中期分析中，我们得出结论：1）特异性去除同种异体反应性是在单倍体不相合情况下预防aGVHD的有效方法；2）关于免疫重建的数据表明，输注的T细胞确实存活并扩增。必须纳入更多患者以确定最佳输注T细胞数量。
