Allotransplantation Section, Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Biol Blood Marrow Transplant. 2011 Dec;17(12):1846-54. doi: 10.1016/j.bbmt.2011.05.017. Epub 2011 May 30.
We evaluated an ex vivo photodepletion (PD) technique to selectively deplete graft-versus-host disease (GVHD) alloreacting T cells given to 24 human leukocyte antigen (HLA)-identical sibling stem cell transplantation (SCT) recipients. Donor lymphocytes were activated by 72-hour exposure to irradiated in vitro expanded recipient T lymphocytes and pulsed with a TH9402 photosensitizer. Alloactivated T cells preferentially retaining the photosensitizer were eliminated by light exposure. The PD product showed an inverted CD4(+)/CD8(+) ratio with greatest depletion occurring in the CD4(+) naive and central memory populations. In contrast, the CD8(+) naive and effector cells were relatively conserved, reflecting the differential extrusion of TH9402 by T cell subsets. Cytomegalovirus reactive T cells were reduced in the PD product and in recipient blood 100 days after SCT when compared with contemporaneous HLA-identical sibling donor T cell-depleted SCT recipients. Although PD SCT recipients experienced similar absolute lymphocyte counts during the first 100 days after SCT, they achieved 100% donor T cell chimerism more rapidly and had higher CD8(+) naive T cell counts early after SCT. SCT recipients of PD products with the lowest CD4 central memory content had the highest risk of developing chronic GVHD (cGVHD) (P = .04) and a poorer survival (P = .03). Although the persistence of CD8(+) naive T cells may have contributed to important antileukemia responses resulting in a relatively low relapse rate, our findings emphasize the role of donor memory T cells and CD4 cells in establishing immune competence post-SCT. Although PD is associated with excellent outcomes in the haploidentical setting, the low frequency of alloactivations in HLA-matched pairs makes the PD approach used by our group for allodepletion in HLA-matched sibling transplantations an inefficient technique.
我们评估了一种离体光耗竭（PD）技术，用于选择性耗竭异体反应性 T 细胞，该技术用于 24 例人类白细胞抗原（HLA）完全匹配的同胞干细胞移植（SCT）受者。供体淋巴细胞通过 72 小时暴露于辐照的体外扩增的受者 T 淋巴细胞并被 TH9402 光敏剂脉冲激活。优先保留光敏剂的同种激活 T 细胞通过光照消除。PD 产物显示出倒置的 CD4(+)/CD8(+)比值，其中 CD4(+)幼稚和中央记忆群体的耗竭最大。相比之下，CD8(+)幼稚和效应细胞相对保留，这反映了 T 细胞亚群对 TH9402 的不同挤出。与同期 HLA 完全匹配的同胞供体 T 细胞耗竭 SCT 受者相比，SCT 后 100 天 PD 产物和受者血液中的巨细胞病毒反应性 T 细胞减少。尽管 PD SCT 受者在 SCT 后 100 天内经历了类似的绝对淋巴细胞计数，但他们更快地实现了 100%供体 T 细胞嵌合体，并且在 SCT 后早期具有更高的 CD8(+)幼稚 T 细胞计数。PD 产物中 CD4 中央记忆含量最低的 SCT 受者发生慢性移植物抗宿主病（cGVHD）的风险最高（P =.04），生存质量较差（P =.03）。尽管 CD8(+)幼稚 T 细胞的持续存在可能有助于导致相对较低复发率的重要抗白血病反应，但我们的发现强调了供体记忆 T 细胞和 CD4 细胞在 SCT 后建立免疫能力的作用。尽管 PD 在单倍体不相容的情况下与良好的结果相关，但 HLA 匹配对中同种激活的频率较低，使得我们小组在 HLA 匹配的同胞移植中用于同种耗竭的 PD 方法成为一种低效技术。
