Department of Immunology & Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
Blood. 2011 Nov 3;118(18):5011-20. doi: 10.1182/blood-2011-03-340315. Epub 2011 Aug 19.
Allogeneic hematopoietic cell transplantation (HCT) is effective therapy for hematologic malignancies through T cell-mediated GVL effects. However, HCT benefits are frequently offset by the destructive GVHD, which is also induced by donor T cells. Naive Th can differentiate into Th1 and Th17 subsets and both can mediate GVHD after adoptive transfer into an allogeneic host. Here we tested the hypothesis that blockade of Th1 and Th17 differentiation is required to prevent GVHD in mice. T cells with combined targeted disruption of T-bet and RORγt have defective differentiation toward Th1 and Th17 and skewed differentiation toward Th2 and regulatory phenotypes, and caused ameliorated GVHD in a major MHC-mismatched model of HCT. GVL effects mediated by granzyme-positive CD8 T cells were largely preserved despite T-bet and RORγt deficiency. These data indicate that GVHD can be prevented by targeting Th1 and Th17 transcription factors without offsetting GVL activity.
同种异体造血细胞移植（HCT）通过 T 细胞介导的移植物抗肿瘤效应是治疗血液系统恶性肿瘤的有效方法。然而，HCT 的益处经常被破坏性的移植物抗宿主病（GVHD）所抵消，GVHD 也是由供体细胞 T 细胞诱导的。初始 Th 可以分化为 Th1 和 Th17 亚群，两者在同种异体宿主中过继转移后均可介导 GVHD。在这里，我们检验了这样一个假设，即阻断 Th1 和 Th17 的分化是预防小鼠 GVHD 的必要条件。T 细胞中 T-bet 和 RORγt 的靶向破坏导致其向 Th1 和 Th17 的分化缺陷和向 Th2 和调节表型的偏向分化，并且在主要 MHC 错配的 HCT 模型中导致 GVHD 的改善。尽管 T-bet 和 RORγt 缺乏，但由颗粒酶阳性 CD8 T 细胞介导的 GVL 效应得到了很大的保留。这些数据表明，通过靶向 Th1 和 Th17 转录因子，可以在不影响 GVL 活性的情况下预防 GVHD。
