Michálek J, Collins R H, Vitetta E S
Cancer Immunobiology Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390 USA.
Neoplasma. 2003;50(4):296-9.
Allogeneic hematopoietic stem cell transplantation is the treatment of choice for many hematological malignancies. Its efficacy is limited by graft-versus-host disease (GVHD), the leading cause of post-transplant morbidity and mortality. GVHD is mediated by a subpopulation of T cells in the stem cell graft. Ex vivo T cell depletion of all T cells of the graft can prevent development of GVHD but can lead to a delay in immune reconstitution and an increase of potentially lethal opportunistic infections and leukemic relapses. Hypothetically, an approach that enables a selective depletion of the alloreactive donor T cells that cause GVHD while preserving third party (anti-leukemic and anti-microbial) reactivity would be optimal for recipients of HSCT. Our preliminary data demonstrated that an anti-CD25 immunotoxin, which reacts with a cell surface activation antigen, can selectively deplete alloreactive donor T cells activated by non-leukemic recipient white blood cells while preserving the beneficial third-party reactivity in vitro. In this report we describe a method for clinical-scale ex vivo selective depletion of alloreactive donor T cells using the anti-CD25 immunotoxin, RFT5-SMPT-dgRTA. Two logs of alloreactive T cells could be selectively depleted while preserving third party reactivity. This method was reproducible in 10 pre-clinical experiments with 8 HLA-mismatched healthy volunteer pairs and 2 HLA-matched sibling donor/patient pairs.
异基因造血干细胞移植是许多血液系统恶性肿瘤的首选治疗方法。其疗效受到移植物抗宿主病（GVHD）的限制，GVHD是移植后发病和死亡的主要原因。GVHD由干细胞移植物中的T细胞亚群介导。对移植物中的所有T细胞进行体外T细胞清除可预防GVHD的发生，但可能导致免疫重建延迟以及潜在致命性机会性感染和白血病复发增加。假设，一种能够选择性清除引起GVHD的同种异体反应性供体T细胞，同时保留第三方（抗白血病和抗微生物）反应性的方法，对于造血干细胞移植受者来说将是最佳的。我们的初步数据表明，一种与细胞表面活化抗原反应的抗CD25免疫毒素，能够在体外选择性清除由非白血病受者白细胞激活的同种异体反应性供体T细胞，同时保留有益的第三方反应性。在本报告中，我们描述了一种使用抗CD25免疫毒素RFT5-SMPT-dgRTA进行临床规模体外选择性清除同种异体反应性供体T细胞的方法。可以选择性清除两个对数的同种异体反应性T细胞，同时保留第三方反应性。该方法在10个临床前实验中具有可重复性，这些实验涉及8对HLA不匹配的健康志愿者和2对HLA匹配的同胞供体/患者对。
