Department of Microbiology, Ewha Womans University School of Medicine, Ewha Medical Research Center, Seoul, Republic of Korea.
Biochem Biophys Res Commun. 2012 Oct 5;426(4):558-64. doi: 10.1016/j.bbrc.2012.08.126. Epub 2012 Sep 6.
Allogenic bone marrow transplantation (BMT), an important treatment for hematological malignancies, is often complicated by graft-versus-host disease (GVHD). Suppression of GVHD is associated with the unwanted diminishment of the graft-versus-leukemia (GVL) response. The aim of this study was to maintain the benefits of GVL during GVHD suppression through isolated blockade of T-cell migration factors. To this end, we developed a murine model of B-cell leukemia, which was treated with BMT to induce GVHD. Within this model, functional blockade of MIP-2/CXCR2 was analyzed by observing proteomic, histologic and clinical variables of GVHD manifestation. Luminex assay of collected tissue identified several cytokines [granulocyte colony-stimulating factor (G-CSF), keratinocyte-derived chemokine (KC), macrophage inflammatory protein-2 (MIP-2), and interleukin-23 (IL-23)] that were upregulated during GHVD, but reduced by neutralizing the MIP-2/CXCR2 axis. In addition, donor T-cell blockade of CXCR2 combined with recipient administration of anti-MIP-2 caused a significant decrease in GVHD while preserving the GVL response. We propose that blocking the MIP-2/CXCR2 axis represents a novel strategy to separate the toxicity of GVHD from the beneficial effects of GVL after allogenic BMT.
同种异体骨髓移植（BMT）是治疗血液系统恶性肿瘤的重要手段，但常并发移植物抗宿主病（GVHD）。GVHD 的抑制与移植物抗白血病（GVL）反应的意外减弱有关。本研究旨在通过隔离阻断 T 细胞迁移因子来维持 GVHD 抑制期间 GVL 的益处。为此，我们建立了一种 B 细胞白血病的小鼠模型，通过 BMT 诱导 GVHD。在该模型中，通过观察 GVHD 表现的蛋白质组学、组织学和临床变量来分析 MIP-2/CXCR2 的功能阻断。对收集的组织进行 Luminex 分析鉴定了几种细胞因子[粒细胞集落刺激因子（G-CSF）、角质形成细胞衍生的趋化因子（KC）、巨噬细胞炎症蛋白-2（MIP-2）和白细胞介素-23（IL-23）]，这些细胞因子在 GVHD 期间上调，但通过中和 MIP-2/CXCR2 轴而减少。此外，CXCR2 阻断的供体细胞与抗 MIP-2 的受者给药相结合，可显著降低 GVHD，同时保留 GVL 反应。我们提出，阻断 MIP-2/CXCR2 轴代表了一种新策略，可以在同种异体 BMT 后将 GVHD 的毒性与 GVL 的有益作用分开。
