Department of Immunology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
Department of Pediatrics, Willem-Alexander Children's Hospital, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
Cells. 2021 Apr 30;10(5):1077. doi: 10.3390/cells10051077.
In the context of hematopoietic stem cell (HSC) transplantation, conditioning with myelo- and immune-ablative agents is used to eradicate the patient's diseased cells, generate space in the marrow and suppress immune reactions prior to the infusion of donor HSCs. While conditioning is required for effective and long-lasting HSC engraftment, currently used regimens are also associated with short and long-term side effects on extramedullary tissues and even mortality. Particularly in patients with severe combined immunodeficiency (SCID), who are generally less than 1-year old at the time of transplantation and often suffer from existing comorbidities. There is a pressing need for development of alternative, less toxic conditioning regimens. Hence, we here aimed to improve efficacy of currently used myeloablative protocols by combining busulfan with stem-cell niche-directed therapeutic agents (G-CSF or plerixafor) that are approved for clinical use in stem cell mobilization. T, B and myeloid cell recovery was analyzed in humanized NSG mice after different conditioning regimens. Increasing levels of human leukocyte chimerism were observed in a busulfan dose-dependent manner, showing comparable immune recovery as with total body irradiation in CD34-transplanted NSG mice. Notably, a better T cell reconstitution compared to TBI was observed after busulfan conditioning not only in NSG mice but also in SCID mouse models. Direct effects of reducing the stem cell compartment in the bone marrow were observed after G-CSF and plerixafor administration, as well as in combination with low doses of busulfan. Unfortunately, these direct effects on the stem population in the bone marrow were not reflected in increased human chimerism or immune recovery after CD34 transplantation in NSG mice. These results indicate moderate potential of reduced conditioning regimens for clinical use relevant for all allogeneic transplants.
在造血干细胞（HSC）移植的背景下，使用骨髓和免疫消融剂进行预处理，以消除患者的病变细胞，在输注供体 HSC 前在骨髓中腾出空间并抑制免疫反应。虽然预处理对于有效的、长期的 HSC 植入是必要的，但目前使用的方案也与骨髓外组织的短期和长期副作用甚至死亡率有关。特别是在严重联合免疫缺陷（SCID）患者中，他们在移植时通常不到 1 岁，并且经常患有现有合并症。迫切需要开发替代的、毒性较小的预处理方案。因此，我们旨在通过将白消安与已批准用于干细胞动员的干细胞龛定向治疗剂（G-CSF 或普乐沙福）联合使用，来提高目前使用的骨髓消融方案的疗效。在不同预处理方案后，在人源化 NSG 小鼠中分析了 T、B 和髓样细胞的恢复情况。在白消安剂量依赖性的方式中观察到人类白细胞嵌合度的增加，在 CD34 移植的 NSG 小鼠中显示出与全身照射相当的免疫恢复。值得注意的是，与 TBI 相比，在白消安预处理后观察到的 T 细胞重建更好，不仅在 NSG 小鼠中，而且在 SCID 小鼠模型中也是如此。在 G-CSF 和普乐沙福给药后，以及与低剂量白消安联合使用后，观察到骨髓中干细胞池的直接减少。不幸的是，这些在骨髓中的干细胞群体的直接作用并没有反映在 NSG 小鼠 CD34 移植后增加的人类嵌合体或免疫恢复中。这些结果表明，减少预处理方案具有适度的潜力，可用于所有同种异体移植。
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