Short-term KRP203 and posttransplant cyclophosphamide for graft-versus-host disease prophylaxis.
Short-term KRP203 and posttransplant cyclophosphamide for graft-versus-host disease prophylaxis.
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短期 KRP203 和移植后环磷酰胺用于预防移植物抗宿主病。
DOI：
10.1038/s41409-019-0733-8
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Teshima T.
中科院分区：
文献类型：
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作者：
Yokoyama E;Hashimoto D;Hayase E;Ara T;Ogasawara R;Takahashi S;Ohigashi H;Tateno T;Hasegawa Y;Chen X;Teshima T.
移植后大剂量环磷酰胺（PTCY）已越来越多地用于HLA半相合或相合造血干细胞移植（SCT）后的移植物抗宿主病（GVHD）预防。然而，单独的PTCY是不够的，需要额外的免疫抑制剂，如钙调磷酸酶抑制剂。在目前的研究中，我们评估了一种新的GVHD预防与PTCY联合短期KRP 203的效果，KRP 203是一种鞘氨醇-1-磷酸受体1的选择性激动剂，可调节小鼠次级淋巴器官（SLO）中淋巴细胞的排出。短期口服KRP 203单独诱导供体T细胞在SLO中的凋亡，并改善GVHD。与环孢菌素相比，KRP 203的施用显著保留了移植物抗白血病效应。第0至+4天的KRP 203和第+3天的PTCY的组合协同抑制供体T细胞迁移到肠和皮肤中，并且比单独的PTCY更有效地改善GVHD。短期KRP 203和PTCY的组合是一种有前途的新的无钙调神经磷酸酶的HLA半相合SCT中的GVHD预防。
Posttransplant high-dose cyclophosphamide (PTCY) has been increasingly used as graft-versus-host disease (GVHD) prophylaxis after HLA-haploidentical or matched hematopoietic stem cell transplantation (SCT). However, PTCY alone is insufficient and requires additional immunosuppressants such as calcineurin inhibitors. In the current study, we evaluated effects of a novel GVHD prophylaxis with PTCY in combination with short-term KRP203, a selective agonist of sphingosine-1-phosphate receptor 1 that regulates egress of lymphocytes from the secondary lymphoid organs (SLOs) in mice. Short-term oral administration of KRP203 alone induced apoptosis of donor T cells in the SLOs and ameliorated GVHD. Administration of KRP203 significantly preserved graft-versus-leukemia effects compared to cyclosporin. A combination of KRP203 on days 0 to +4 and PTCY on day +3 synergistically suppressed donor T-cell migration into the intestine and skin, and ameliorated GVHD more potently than PTCY alone. A combination of short-term KRP203 and PTCY is a promising novel calcineurin-free GVHD prophylaxis in HLA-haploidentical SCT.