Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
J Exp Med. 2011 May 9;208(5):1069-82. doi: 10.1084/jem.20101709. Epub 2011 May 2.
Acute graft-versus-host disease (GVHD) results from the attack of host tissues by donor allogeneic T cells and is the most serious limitation of allogeneic hematopoietic cell transplantation (allo-HCT). Host antigen-presenting cells are thought to control the priming of alloreactive T cells and the induction of acute GVHD after allo-HCT. However, whereas the role of host DC in GVHD has been established, the contribution of host macrophages to GVHD has not been clearly addressed. We show that, in contrast to DC, reducing of the host macrophage pool in recipient mice increased donor T cell expansion and aggravated GVHD mortality after allo-HCT. We also show that host macrophages that persist after allo-HCT engulf donor allogeneic T cells and inhibit their proliferation. Conversely, administration of the cytokine CSF-1 before transplant expanded the host macrophage pool, reduced donor T cell expansion, and improved GVHD morbidity and mortality after allo-HCT. This study establishes the unexpected key role of host macrophages in inhibiting GVHD and identifies CSF-1 as a potential prophylactic therapy to limit acute GVHD after allo-HCT in the clinic.
急性移植物抗宿主病（GVHD）是由供体同种异体 T 细胞攻击宿主组织引起的，是异基因造血细胞移植（allo-HCT）最严重的限制因素。宿主抗原呈递细胞被认为可以控制同种反应性 T 细胞的启动和 allo-HCT 后急性 GVHD 的诱导。然而，尽管宿主树突状细胞（DC）在 GVHD 中的作用已得到确立，但宿主巨噬细胞在 GVHD 中的贡献尚未得到明确解决。我们发现，与 DC 相反，减少受体小鼠中的宿主巨噬细胞池会增加供体 T 细胞的扩增，并加重 allo-HCT 后的 GVHD 死亡率。我们还发现，在 allo-HCT 后持续存在的宿主巨噬细胞吞噬供体同种异体 T 细胞并抑制其增殖。相反，移植前施用细胞因子 CSF-1 可扩增宿主巨噬细胞池，减少供体 T 细胞扩增，并改善 allo-HCT 后的 GVHD 发病率和死亡率。这项研究确立了宿主巨噬细胞在抑制 GVHD 中的意外关键作用，并确定 CSF-1 作为一种潜在的预防疗法，可在临床上限制 allo-HCT 后的急性 GVHD。
