University Children's Hospital, Ulm, Germany.
Leukemia. 2011 May;25(5):848-55. doi: 10.1038/leu.2011.16. Epub 2011 Feb 18.
Mature donor-derived T cells in allogeneic bone marrow (BM) transplants mediate the graft-versus-tumor (GVT) effect by recognizing alloantigens on leukemic cells. However, alloantigen reactivity towards non-malignant tissues also induces graft-versus-host disease (GVHD). Defining T-cell subpopulations that mediate the GVT effect in the absence of GVHD induction remains a major challenge in allogeneic BM transplantation. In this study, we show that in vitro-generated alloantigen-specific CD8(+) cytotoxic T cells (CTLs) established by weekly stimulation with alloantigen-expressing antigen-presenting cells did not induce GVHD in two major histocompatibility complex-mismatched BM transplantation models, where induction of lethal GVHD is dependent on the presence of either CD4(+) or CD8(+) T cells. Despite their strong alloantigen specificity, transplantation of CTLs did not induce the expression of GVHD-associated cytokines IFN-γ and TNF-α or clinical or histological signs of GVHD, and lead to a survival rate of above 90%. However, transplantation of unstimulated CD8(+) T cells, which were not primed by the alloantigen in vitro, induced GVHD in both the transplantation models. Although CTLs were impaired in GVHD induction, they efficiently eradicated Bcr-Abl-transformed B-cell leukemias or mastocytomas. Thus, in vitro-derived CTLs might be useful for optimizing anti-tumor therapy in the absence of GVHD induction.
同种异体骨髓 (BM) 移植中的成熟供体衍生 T 细胞通过识别白血病细胞上的同种异体抗原来介导移植物抗肿瘤 (GVT) 效应。然而，对非恶性组织的同种异体抗原反应也会诱导移植物抗宿主病 (GVHD)。定义在不诱导 GVHD 的情况下介导 GVT 效应的 T 细胞亚群仍然是同种异体 BM 移植中的主要挑战。在这项研究中，我们表明，通过每周用表达同种异体抗原的抗原呈递细胞刺激产生的体外生成的同种异体抗原特异性 CD8(+)细胞毒性 T 细胞 (CTL)，在两种主要组织相容性复合物不匹配的 BM 移植模型中不会诱导 GVHD，其中致死性 GVHD 的诱导依赖于 CD4(+)或 CD8(+) T 细胞的存在。尽管 CTL 具有很强的同种异体抗原特异性，但 CTL 的移植并未诱导 GVHD 相关细胞因子 IFN-γ 和 TNF-α 的表达或出现临床或组织学 GVHD 迹象，并且导致存活率超过 90%。然而，未在体外通过同种异体抗原刺激的未刺激的 CD8(+) T 细胞的移植在这两种移植模型中均诱导 GVHD。尽管 CTL 在诱导 GVHD 方面受损，但它们能有效地根除 Bcr-Abl 转化的 B 细胞白血病或肥大细胞瘤。因此，体外衍生的 CTL 可能有助于在不诱导 GVHD 的情况下优化抗肿瘤治疗。
