α-1-Antitrypsin (AAT)-modified donor cells suppress GVHD but enhance the GVL effect: a role for mitochondrial bioenergetics
α-1-Antitrypsin (AAT)-modified donor cells suppress GVHD but enhance the GVL effect: a role for mitochondrial bioenergetics
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DOI：
10.1182/blood-2014-04-570440
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发表时间：
2014-10-30
期刊：
影响因子：
20.3
通讯作者：
Deeg, H. Joachim
中科院分区：
文献类型：
--
作者：
Marcondes, A. Mario;Karoopongse, Ekapun;Deeg, H. Joachim
造血细胞移植在许多患者中是治愈的。然而，由异基因反应供体细胞引发的移植物抗宿主病(GVHD)仍然是一个主要的并发症。在这里，我们显示了人类供者血浆α-1-抗胰蛋白酶(AAT)水平与受者发生急性移植物抗宿主病(GVHD)之间的负相关(n=111；P=.0006)。在小鼠模型中，用人AAT治疗移植供者后，受者IL-10信使RNA和CD8(+)CD11c(+)CD205(+)主要组织相容性复合体II+树突状细胞(DCs)增加，从而预防或减轻急性GVHD。去除DC(在AAT处理的CD11c-DTR供者中)使CD4(+)CD25(+)FoxP3(+)调节性T细胞减少到三分之一，并取消了抗GVHD的作用。供者的AAT治疗维持甚至增强了供者细胞对A20肿瘤细胞的移植物抗白血病(GVL)效应，这种作用是通过扩增表达NK1.1(+)、CD49B(+)、CD122(+)、CD335(+)NKG2D的自然杀伤(NK)细胞来实现的。阻断NKG2D可显著抑制GVL效应。代谢分析显示，NK1.1(+)细胞、CD4(+)CD25(+)FoxP3(+)T细胞和CD11c(+)DC具有高糖酵解-高氧化磷酸化特征，但对效应性T细胞不存在，提示AAT具有细胞类型特异性作用。因此，通过改变代谢，AAT在增强GVL效应的同时，发挥有效的GVHD保护作用。
Hematopoietic cell transplantation is curative in many patients. However, graft-versus-host disease (GVHD), triggered by alloreactive donor cells, has remained a major complication. Here, we show an inverse correlation between plasma alpha-1-antitrypsin (AAT) levels in human donors and the development of acute GVHD in the recipients (n=111; P=.0006). In murine models, treatment of transplant donors with human AAT resulted in an increase in interleukin-10 messenger RNA and CD8(+)CD11c(+)CD205(+) major histocompatibility complex class II+ dendritic cells (DCs), and the prevention or attenuation of acute GVHD in the recipients. Ablation of DCs (in AAT-treated CD11c-DTR donors) decreased CD4(+)CD25(+) FoxP3(+) regulatory T cells to one-third and abrogated the anti-GVHD effect. The graft-versus-leukemia (GVL) effect of donor cells (against A20 tumor cells) was maintained or even enhanced with AAT treatment of the donor, mediated by an expanded population of NK1.1(+), CD49B(+), CD122(+), CD335(+) NKG2D-expressing natural killer (NK) cells. Blockade of NKG2D significantly suppressed the GVL effect. Metabolic analysis showed a high glycolysis-high oxidative phosphorylation profile for NK1.1(+) cells, CD4(+)CD25(+)FoxP3(+) T cells, and CD11c(+) DCs but not for effector T cells, suggesting a cell type-specific effect of AAT. Thus, via altered metabolism, AAT exerts effective GVHD protection while enhancing GVL effects.