Prigozhina Tatyana B, Elkin Gregory, Khitrin Sofia, Slavin Shimon
Department of Bone Marrow Transplantation, Hadassah University Hospital, Jerusalem, Israel.
Exp Hematol. 2008 Dec;36(12):1750-9. doi: 10.1016/j.exphem.2008.07.002. Epub 2008 Sep 21.
Previously, we documented that conditioning based on donor-specific cell transfusion (DST) and subsequent selective depletion of activated donor-reactive cells by cyclophosphamide (CY) facilitates alloengraftment in a murine transplantation model. Transplantation event represents a strong immunogenic stimulus for host-reactive donor T cells that induce graft-vs-host disease (GVHD). Therefore, in this study, we addressed the question of whether a single posttransplantation CY administration (CY2) can prevent acute GVHD-related mortality without compromising engraftment of allogeneic transplant.
Splenocyte-enriched C57BL/6 bone marrow was transplanted to BALB/c recipients after mild irradiation, and conditioning with DST and 100 mg/kg CY. Following transplantation, recipients were left untreated or given on a specified day a single CY2 injection (50 mg/kg). All animals were monitored for survival, chimerism, and clinical signs of GVHD. Experimental mice that received BCL1 leukemia cells before transplantation were monitored for leukemia-related mortality as well.
Animals that received no CY2 after transplantation died of acute GVHD. A single low-dose CY2 treatment within the first 5 days after transplantation prevented mortality in most recipients. However, only CY2 administration on days +1 or +5 preserved chimerism. Most chimeras survived GVHD-free for >200 days. Prolonged persistence of host-reactive T cells in mice (CY2 on day +5) permitted a reduction to be made in engraftment-essential irradiation dose and preserved a strong graft-vs-leukemia effect of transplantation.
Acute GVHD can be prevented in mice by a single properly timed posttransplantation low-dose CY administration.
此前，我们记录了基于供体特异性细胞输注（DST）的预处理以及随后用环磷酰胺（CY）选择性清除活化的供体反应性细胞，可促进小鼠移植模型中的异基因移植。移植事件对诱导移植物抗宿主病（GVHD）的宿主反应性供体T细胞而言是一种强烈的免疫原性刺激。因此，在本研究中，我们探讨了移植后单次给予CY（CY2）能否预防急性GVHD相关死亡，同时又不影响异基因移植的植入。
轻度照射后，将富含脾细胞的C57BL/6骨髓移植到BALB/c受体，并进行DST和100mg/kg CY预处理。移植后，受体不进行处理或在指定日期给予单次CY2注射（50mg/kg）。监测所有动物的生存情况、嵌合现象和GVHD的临床体征。对移植前接受BCL1白血病细胞的实验小鼠也监测白血病相关死亡情况。
移植后未接受CY2的动物死于急性GVHD。移植后前5天内单次低剂量CY2治疗可防止大多数受体死亡。然而，仅在第+1天或第+5天给予CY2可维持嵌合现象。大多数嵌合体无GVHD存活超过200天。小鼠体内宿主反应性T细胞的长期存在（第+5天给予CY2）使得可以降低对植入至关重要的照射剂量，并保留移植的强大移植物抗白血病效应。
移植后单次适时给予低剂量CY可预防小鼠急性GVHD。
