Division of Experimental Hematology and Cancer Biology and.
Division of Bone Marrow Transplantation and Immune Deficiency, Cancer and Blood Disease Institute, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, Ohio, USA.
JCI Insight. 2016 Sep 22;1(15):e88181. doi: 10.1172/jci.insight.88181.
Transgenic expression of key myelosupportive human cytokines in immune-deficient mice corrects for the lack of cross-species activities of stem cell factor (SCF), IL-3, and GM-CSF. When engrafted with human umbilical cord blood (UCB), these triple-transgenic mice produce BM and spleen grafts with much higher myeloid composition, relative to nontransgenic controls. Shortly after engraftment with UCB, these mice develop a severe, fatal macrophage activation syndrome (MAS) characterized by a progressive drop in rbc numbers, increased reticulocyte counts, decreased rbc half-life, progressive cytopenias, and evidence of chronic inflammation, including elevated human IL-6. The BM becomes strikingly hypocellular, and spleens are significantly enlarged with evidence of extramedullary hematopoiesis and activated macrophages engaged in hemophagocytosis. This manifestation of MAS does not respond to lymphocyte-suppressive therapies such as steroids, i.v. immunoglobulin, or antibody-mediated ablation of human B and T cells, demonstrating a lymphocyte-independent mechanism of action. In contrast, elimination of human myeloid cells using gemtuzumab ozogamicin (anti-CD33) completely reversed the disease. Additionally, the IL-6R antibody tocilizumab delayed progression and prolonged lifespan. This new model of MAS provides an opportunity for investigation of the mechanisms driving this disease and for the testing of directed therapies in a humanized mouse.
在免疫缺陷小鼠中转基因表达关键的人类骨髓支持细胞因子可纠正干细胞因子 (SCF)、IL-3 和 GM-CSF 缺乏种间活性的问题。当与人类脐带血 (UCB) 共移植时，这些三重转基因小鼠产生的 BM 和脾脏移植物具有更高的髓系组成，与非转基因对照相比。在 UCB 移植后不久，这些小鼠会发展为严重的、致命的巨噬细胞活化综合征 (MAS)，其特征是红细胞数量逐渐下降、网织红细胞计数增加、红细胞半衰期缩短、进行性血细胞减少以及慢性炎症的证据，包括升高的人 IL-6。BM 变得明显细胞减少，脾脏显著肿大，有髓外造血和参与噬血细胞作用的活化巨噬细胞的证据。这种 MAS 的表现形式不会对淋巴细胞抑制治疗（如类固醇、静脉注射免疫球蛋白或抗体介导的人 B 和 T 细胞消融）产生反应，表明其作用机制与淋巴细胞无关。相比之下，使用吉妥珠单抗奥佐米星（抗-CD33）消除人类髓系细胞可完全逆转疾病。此外，IL-6R 抗体托珠单抗可延缓疾病进展并延长生存期。这种新的 MAS 模型为研究驱动这种疾病的机制以及在人源化小鼠中测试靶向治疗提供了机会。
