Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia.
Biostatistics and Bioinformatics Shared Resource, Winship Cancer Institute of Emory University, Atlanta, Georgia.
Biol Blood Marrow Transplant. 2019 Jun;25(6):1075-1084. doi: 10.1016/j.bbmt.2018.11.029. Epub 2018 Nov 29.
A higher number of donor plasmacytoid dendritic cells (pDCs) is associated with increased survival and reduced graft-versus-host disease (GVHD) in human recipients of unrelated donor bone marrow (BM) grafts, but not granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood grafts. We show that in murine models, donor BM pDCs are associated with increased survival and decreased GVHD compared with G-CSF-mobilized pDCs. To increase the content of pDCs in BM grafts, we studied the effect of FMS-like tyrosine kinase 3 ligand (Flt3L) treatment of murine BM donors on transplantation outcomes. Flt3L treatment (300 μg/kg/day) resulted in a schedule-dependent increase in the content of pDCs in the BM. Mice treated on days -4 and -1 had a >5-fold increase in pDC content without significant changes in numbers of HSCs, T cells, B cells, and natural killer cells in the BM graft. In an MHC-mismatched murine transplant model, recipients of Flt3L-treated T cell-depleted (TCD) BM (TCD F-BM) and cytokine-untreated T cells had increased survival and decreased GVHD scores with fewer Th1 and Th17 polarized T cells post-transplantation compared with recipients of equivalent numbers of untreated donor TCD BM and T cells. Gene array analyses of pDCs from Flt3L-treated human and murine donors showed up-regulation of adaptive immune pathways and immunoregulatory checkpoints compared with pDCs from untreated BM donors. Transplantation of TCD F-BM plus T cells resulted in no loss of the graft-versus-leukemia (GVL) effect compared with grafts from untreated donors in 2 murine GVL models. Thus, Flt3L treatment of BM donors is a novel method for increasing the pDC content in allografts, improving survival, and decreasing GVHD without diminishing the GVL effect.
供者浆细胞样树突状细胞（pDC）数量较高与无关供者骨髓（BM）移植受者的存活率增加和移植物抗宿主病（GVHD）减少相关，但与粒系集落刺激因子（G-CSF）动员的外周血移植物无关。我们表明，在小鼠模型中，与 G-CSF 动员的 pDC 相比，供者 BM pDC 与存活率增加和 GVHD 减少相关。为了增加 BM 移植物中 pDC 的含量，我们研究了 FMS 样酪氨酸激酶 3 配体（Flt3L）处理供者 BM 对移植结果的影响。Flt3L 处理（300μg/kg/天）导致 BM 中 pDC 含量呈时间依赖性增加。在第-4 天和第-1 天接受治疗的小鼠，pDC 含量增加了 5 倍以上，而 BM 移植物中的造血干细胞（HSCs）、T 细胞、B 细胞和自然杀伤细胞（NK 细胞）数量没有明显变化。在 MHC 错配的小鼠移植模型中，与接受未经处理的供者 TCD BM 和 T 细胞的受者相比，接受 Flt3L 处理的 T 细胞耗竭（TCD）BM（TCD F-BM）和未处理的细胞因子 T 细胞的受者具有更高的存活率和更低的 GVHD 评分，并且移植后 Th1 和 Th17 极化 T 细胞更少。与未经处理的 BM 供者的 pDC 相比，来自 Flt3L 处理的人类和小鼠供者的 pDC 的基因阵列分析显示适应性免疫途径和免疫调节检查点上调。与接受未经处理的供者的移植物相比，TCD F-BM 加 T 细胞的移植在 2 种小鼠 GVL 模型中并未导致移植物抗白血病（GVL）效应丧失。因此，BM 供者的 Flt3L 处理是一种增加同种异体移植物中 pDC 含量、提高存活率和降低 GVHD 而不降低 GVL 效应的新方法。
