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.

移植后大剂量环磷酰胺（PTCY）已越来越多地用作HLA单倍型或匹配的造血干细胞移植（SCT）后的移植物抗宿主病（GVHD）预防。但是，仅靠PTCY是不够的，需要其他的免疫抑制剂，例如钙调神经磷酸酶抑制剂。在当前研究中，我们评估了PTCY与短期KRP203的结合对新型GVHD预防的效果，短期KRP203是鞘氨醇-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）的淋巴细胞流出。单独短期口服KRP203可以诱导SLO中供体T细胞凋亡，并改善GVHD。与环孢菌素相比，施用KRP203可显着保留移植物抗白血病作用。在第0至+4天的KRP203和在+3天的PTCY的组合可协同抑制供体T细胞迁移到肠道和皮肤，并且比单独使用PTCY更有效地改善GVHD。短期KRP203和PTCY的结合在HLA单倍体SCT中是一种有希望的新型无钙调神经磷酸的GVHD预防药物。