Martin P J, Hansen J A, Buckner C D, Sanders J E, Deeg H J, Stewart P, Appelbaum F R, Clift R, Fefer A, Witherspoon R P
Blood. 1985 Sep;66(3):664-72.
We report results of a pilot study designed to evaluate the effects of in vitro depletion of T lymphocytes from donor marrow in patients receiving HLA-identical marrow grafts for treatment of hematologic malignancies. Twenty patients aged 31 to 50 years were prepared for transplantation with cyclophosphamide (120 mg/kg) and fractionated total body irradiation (12.0 or 15.75 Gy). All received cyclosporine after grafting. The donor marrows were treated with a mixture of eight murine monoclonal antibodies and rabbit serum complement in a manner that achieved a 2- to 3-log depletion of T cells in most patients. Initial engraftment occurred promptly in 19 of the patients, and only three had clinically significant acute graft-versus-host disease. Depletion of donor T cells, however, was associated with an increased incidence of graft failure, which occurred as late as 244 days after transplantation. Graft failure was transient in one patient but apparently was irreversible in seven others. Three of the seven patients had cytogenetic but not morphological evidence of leukemic relapse at the time of graft failure. All seven patients with irreversible graft failure have died, six after receiving second bone marrow transplants. Seven of the eight cases of graft failure occurred among the 11 patients prepared for transplantation with 12.0 Gy of total-body irradiation, and only one occurred among the nine patients with advanced malignancies who received 15.75 Gy of total-body irradiation. This association with irradiation dose suggests that host factors were partly responsible for the graft failures. Because graft failure seldom occurs in irradiated recipients of unmodified HLA-identical allogeneic marrow transplants, it appears that T cells in the donor marrow may serve a beneficial function in helping to maintain sustained engraftment possibly by eliminating host cells that can cause graft failure. Optimal application of in vitro manipulation of donor marrow as a method for preventing graft-versus-host disease will require more effective immunosuppression of the recipient in order to assure sustained engraftment and function of donor stem cells.
我们报告了一项初步研究的结果，该研究旨在评估在接受 HLA 相同骨髓移植以治疗血液系统恶性肿瘤的患者中，对供体骨髓进行体外 T 淋巴细胞清除的效果。20 名年龄在 31 至 50 岁之间的患者接受了环磷酰胺（120mg/kg）和分次全身照射（12.0 或 15.75Gy）预处理以进行移植。所有患者移植后均接受环孢素治疗。供体骨髓用八种鼠单克隆抗体和兔血清补体的混合物处理，大多数患者的 T 细胞减少了 2 至 3 个对数级。19 名患者迅速出现初始植入，只有 3 名患者发生了具有临床意义的急性移植物抗宿主病。然而，供体 T 细胞的清除与移植失败发生率增加有关，移植失败最晚发生在移植后 244 天。一名患者的移植失败是短暂的，但另外七名患者的移植失败显然是不可逆的。七名患者中有三名在移植失败时具有白血病复发的细胞遗传学证据但无形态学证据。所有七名移植失败不可逆的患者均已死亡，其中六名在接受第二次骨髓移植后死亡。八例移植失败中有七例发生在接受 12.0Gy 全身照射预处理的 11 名患者中，而在接受 15.75Gy 全身照射的九名晚期恶性肿瘤患者中仅发生一例。这种与照射剂量的关联表明宿主因素部分导致了移植失败。由于在接受未修饰的 HLA 相同同种异体骨髓移植的受照射患者中很少发生移植失败，因此似乎供体骨髓中的 T 细胞可能通过消除可导致移植失败的宿主细胞，在帮助维持持续植入方面发挥有益作用。作为预防移植物抗宿主病的一种方法，体外处理供体骨髓的最佳应用将需要对受者进行更有效的免疫抑制，以确保供体干细胞的持续植入和功能。
