Institute of Experimental Immunology,University of Zurich, CH-8057 Zurich, Switzerland.
INSERM U1043-CNRS UMR 5282, Physiopathology Center of Toulouse-Purpan, Toulouse, France.
Sci Transl Med. 2018 Nov 28;10(469). doi: 10.1126/scitranslmed.aat8410.
Allogeneic hematopoietic cell transplantation (allo-HCT) not only is an effective treatment for several hematologic malignancies but can also result in potentially life-threatening graft-versus-host disease (GvHD). GvHD is caused by T cells within the allograft attacking nonmalignant host tissues; however, these same T cells mediate the therapeutic graft-versus-leukemia (GvL) response. Thus, there is an urgent need to understand how to mechanistically uncouple GvL from GvHD. Using preclinical models of full and partial MHC-mismatched HCT, we here show that the granulocyte-macrophage colony-stimulating factor (GM-CSF) produced by allogeneic T cells distinguishes between the two processes. GM-CSF drives GvHD pathology by licensing donor-derived phagocytes to produce inflammatory mediators such as interleukin-1β and reactive oxygen species. In contrast, GM-CSF did not affect allogeneic T cells or their capacity to eliminate leukemic cells, retaining undiminished GvL responses. Last, tissue biopsies and peripheral blood mononuclear cells from patients with grade IV GvHD showed an elevation of GM-CSF-producing T cells, suggesting that GM-CSF neutralization has translational potential in allo-HCT.
异基因造血细胞移植（allo-HCT）不仅是治疗几种血液系统恶性肿瘤的有效方法，而且可能导致危及生命的移植物抗宿主病（GvHD）。GvHD 是由移植物中的 T 细胞攻击非恶性宿主组织引起的；然而，这些相同的 T 细胞介导了治疗性移植物抗白血病（GvL）反应。因此，迫切需要了解如何从机制上分离 GvL 与 GvHD。我们使用全和部分 MHC 错配 HCT 的临床前模型，这里表明，同种异体 T 细胞产生的粒细胞-巨噬细胞集落刺激因子（GM-CSF）区分了这两个过程。GM-CSF 通过许可供体衍生的吞噬细胞产生白细胞介素-1β和活性氧等炎症介质来驱动 GvHD 病理学。相比之下，GM-CSF 不会影响同种异体 T 细胞或其消除白血病细胞的能力，保留未减弱的 GvL 反应。最后，来自患有 4 级 GvHD 的患者的组织活检和外周血单核细胞显示产生 GM-CSF 的 T 细胞升高，表明 GM-CSF 中和在 allo-HCT 中具有转化潜力。
