Bone Marrow Transplantation Program, University of Michigan, Ann Arbor, MI 48109, USA.
Blood. 2011 Jan 6;117(1):299-308. doi: 10.1182/blood-2010-03-271940. Epub 2010 Sep 24.
Graft-versus-host disease (GVHD) remains the major barrier to the success of allogeneic hematopoietic stem cell transplantation (HSCT). GVHD is caused by donor T cells that mediate host tissue injury through multiple inflammatory mechanisms. Blockade of individual effector molecules has limited efficacy in controlling GVHD. Here, we report that Notch signaling is a potent regulator of T-cell activation, differentiation, and function during acute GVHD. Inhibition of canonical Notch signaling in donor T cells markedly reduced GVHD severity and mortality in mouse models of allogeneic HSCT. Although Notch-deprived T cells proliferated and expanded in response to alloantigens in vivo, their ability to produce interleukin-2 and inflammatory cytokines was defective, and both CD4(+) and CD8(+) T cells failed to up-regulate selected effector molecules. Notch inhibition decreased the accumulation of alloreactive T cells in the intestine, a key GVHD target organ. However, Notch-deprived alloreactive CD4(+) T cells retained significant cytotoxic potential and antileukemic activity, leading to improved overall survival of the recipients. These results identify Notch as a novel essential regulator of pathogenic CD4(+) T-cell responses during acute GVHD and suggest that Notch signaling in T cells should be investigated as a therapeutic target after allogeneic HSCT.
移植物抗宿主病（GVHD）仍然是异基因造血干细胞移植（HSCT）成功的主要障碍。GVHD 是由供体 T 细胞通过多种炎症机制介导宿主组织损伤引起的。阻断单个效应分子在控制 GVHD 方面的疗效有限。在这里，我们报告 Notch 信号是急性 GVHD 期间 T 细胞激活、分化和功能的强有力调节剂。在异基因 HSCT 的小鼠模型中，抑制供体 T 细胞中的经典 Notch 信号显著降低了 GVHD 的严重程度和死亡率。尽管 Notch 缺失的 T 细胞在体内对同种异体抗原增殖和扩增，但它们产生白细胞介素 2 和炎症细胞因子的能力有缺陷，CD4(+)和 CD8(+)T 细胞均未能上调选定的效应分子。Notch 抑制减少了同种反应性 T 细胞在肠道中的积累，肠道是 GVHD 的关键靶器官。然而，Notch 缺失的同种反应性 CD4(+)T 细胞仍然保留显著的细胞毒性潜力和抗白血病活性，导致受者的总生存率提高。这些结果表明 Notch 是急性 GVHD 期间致病性 CD4(+)T 细胞反应的新型必需调节剂，并表明 T 细胞中的 Notch 信号应作为异基因 HSCT 后的治疗靶点进行研究。
