Long-Acting IL-33 Mobilizes High-Quality Hematopoietic Stem and Progenitor Cells More Efficiently Than Granulocyte Colony-Stimulating Factor or AMD3100
Long-Acting IL-33 Mobilizes High-Quality Hematopoietic Stem and Progenitor Cells More Efficiently Than Granulocyte Colony-Stimulating Factor or AMD3100
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DOI：
10.1016/j.bbmt.2019.05.030
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发表时间：
2019-08-01
影响因子：
4.3
通讯作者：
Bauzon, Maxine
中科院分区：
文献类型：
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作者：
Alt, Carsten;Yuan, Shujun;Bauzon, Maxine
造血干细胞和祖细胞（HSPCs）的动员在造血细胞移植中越来越重要。目前的动员方法是不够的，因为它们不能动员足够数量的细胞在很大一部分患者中，并且偏向于骨髓免疫重建。因此，一种新的单一药物动员剂，允许更平衡的（髓细胞和淋巴细胞）重建，将非常有利于改善移植结果。在本研究中，我们测试了市售的IL-33分子和设计的IL-33的新变体。这些分子在体外细胞实验和体内动员模型中进行了测试。我们首次观察到IL-33治疗小鼠比临床动员剂粒细胞集落刺激因子（G-CSF）或AMD3100更有效地动员HSPCs和普通髓系祖细胞。我们设计了几种具有相同或更好体外活性的抗氧化IL-33变体。在体内，这些变异比野生型IL-33或G-CSF更有效地动员了HSPCs，有趣的是，也动员了造血干细胞、普通淋巴样祖细胞和内皮祖细胞。然后我们设计了IL-33-Fc融合分子，单剂量足以在4天后显著增加HSPCs的动员。总之，我们的研究结果表明，长效、抗氧化的IL-33可能是HSPC移植的一种新方法。il -33动员的HSPCs与G-CSF和AMD3100动员的细胞不同，这些差异可能导致更好的移植结果。(C) 2019年美国血液和骨髓移植学会。
Mobilization of hematopoietic stem and progenitor cells (HSPCs) has become increasingly important for hematopoietic cell transplantation. Current mobilization approaches are insufficient because they fail to mobilize sufficient numbers of cells in a significant fraction of patients and are biased toward myeloid immune reconstitution. A novel, single drug mobilization agent that allows a more balanced (myeloid and lymphoid) reconstitution would therefore be highly favorable to improve transplantation outcome. In this present study, we tested commercially available IL-33 molecules and engineered novel variants of IL-33. These molecules were tested in cell-based assays in vitro and in mobilization models in vivo. We observed for the first time that IL-33 treatment in mice mobilized HSPCs and common myeloid progenitors more efficiently than clinical mobilizing agents granulocyte colony stimulating factor (G-CSF) or AMD3100. We engineered several oxidation-resistant IL-33 variants with equal or better in vitro activity. In vivo, these variants mobilized HSPCs and, interestingly, also hematopoietic stem cells, common lymphoid progenitor cells, and endothelial progenitor cells more efficiently than wild-type IL-33 or G-CSF. We then engineered an IL-33-Fc fusion molecule, a single dose of which was sufficient to significantly increase the mobilization of HSPCs after 4 days. In conclusion, our findings suggest that long-acting, oxidation resistant IL-33 may be a novel approach for HSPC transplantation. IL-33-mobilized HSPCs differ from cells mobilized with G-CSF and AMD3100, and it is possible that these differences may result in better transplantation outcomes. (C) 2019 American Society for Blood and Marrow Transplantation.